{"article_id": "PMC5075302", "article_text": ["anxiety affects quality of life in those living with parkinson 's disease ( pd ) more so than overall cognitive status , motor deficits , apathy , and depression [ 13 ] .", "although anxiety and depression are often related and coexist in pd patients , recent research suggests that anxiety rather than depression is the most prominent and prevalent mood disorder in pd [ 5 , 6 ] . yet ,", "our current understanding of anxiety and its impact on cognition in pd , as well as its neural basis and best treatment practices , remains meager and lags far behind that of depression .", "overall , neuropsychiatric symptoms in pd have been shown to be negatively associated with cognitive performance .", "for example , higher depression scores have been correlated with lower scores on the mini - mental state exam ( mmse ) [ 8 , 9 ] as well as tests of memory and executive functions ( e.g. , attention ) [ 1014 ] .", "likewise , apathy and anhedonia in pd patients have been associated with executive dysfunction [ 10 , 1523 ] .", "however , few studies have specifically investigated the relationship between anxiety and cognition in pd .", "one study showed a strong negative relationship between anxiety ( both state and trait ) and overall cognitive performance ( measured by the total of the repeatable battery for the assessment of neuropsychological status index ) within a sample of 27 pd patients .", "furthermore , trait anxiety was negatively associated with each of the cognitive domains assessed by the rbans ( i.e. , immediate memory , visuospatial construction , language , attention , and delayed memory ) .", "two further studies have examined whether anxiety differentially affects cognition in patients with left - sided dominant pd ( lpd ) versus right - sided dominant pd ( rpd ) ; however , their findings were inconsistent .", "the first study found that working memory performance was worse in lpd patients with anxiety compared to rpd patients with anxiety , whereas the second study reported that , in lpd , apathy but not anxiety was associated with performance on nonverbally mediated executive functions and visuospatial tasks ( e.g. , tmt - b , wms - iii spatial span ) , while in rpd , anxiety but not apathy significantly correlated with performance on verbally mediated tasks ( e.g. , clock reading test and boston naming test ) .", "furthermore , anxiety was significantly correlated with neuropsychological measures of attention and executive and visuospatial functions . taken together ,", "it is evident that there are limited and inconsistent findings describing the relationship between anxiety and cognition in pd and more specifically how anxiety might influence particular domains of cognition such as attention and memory and executive functioning .", "it is also striking that , to date , no study has examined the influence of anxiety on cognition in pd by directly comparing groups of pd patients with and without anxiety while excluding depression .", "given that research on healthy young adults suggests that anxiety reduces processing capacity and impairs processing efficiency , especially in the central executive and attentional systems of working memory [ 26 , 27 ] , we hypothesized that pd patients with anxiety would show impairments in attentional set - shifting and working memory compared to pd patients without anxiety .", "furthermore , since previous work , albeit limited , has focused on the influence of symptom laterality on anxiety and cognition , we also explored this relationship .", "seventeen pd patients with anxiety and thirty - three pd patients without anxiety were included in this study ( see table 1 ) .", "the cross - sectional data from these participants was taken from a patient database that has been compiled over the past 8 years ( since 2008 ) at the parkinson 's disease research clinic at the brain and mind centre , university of sydney .", "inclusion criteria involved a diagnosis of idiopathic pd according to the united kingdom parkinson 's disease society brain bank criteria   and were confirmed by a neurologist ( sjgl ) .", "patients also had to have an adequate proficiency in english and have completed a full neuropsychological assessment .", "ten patients in this study ( 5 pd with anxiety ; 5 pd without anxiety ) were taking psychotropic drugs ( i.e. , benzodiazepine or selective serotonin reuptake inhibitor ) .", "patients were also excluded if they had other neurological disorders , psychiatric disorders other than affective disorders ( such as anxiety ) , or if they reported a score greater than six on the depression subscale of the hospital anxiety and depression scale ( hads ) .", "thus , all participants who scored within a  depressed  ( hads - d > 6 ) range were excluded from this study , in attempt to examine a refined sample of pd patients with and without anxiety in order to determine the independent effect of anxiety on cognition .", "this research was approved by the human research ethics committee of the university of sydney , and written informed consent was obtained from all participants .", "self - reported hads was used to assess anxiety in pd and has been previously shown to be a useful measure of clinical anxiety in pd .", "a cut - off score of > 8 on the anxiety subscale of the hads ( hads - a ) was used to identify pd cases with anxiety ( pda+ ) , while a cut - off score of < 6 on the hads - a was used to identify pd cases without anxiety ( pda ) .", "this criterion was more stringent than usual ( > 7 cut - off score ) , in effort to create distinct patient groups .", "the neurological evaluation rated participants according to hoehn and yahr ( h&y ) stages   and assessed their motor symptoms using part iii of the revised mds task force unified parkinson 's disease rating scale ( updrs ) . in a similar way", "this was determined by calculating a total left and right score from rigidity items 3035 , voluntary movement items 3643 , and tremor items 5057 from the mds - updrs part iii ( see table 1 ) .", "processing speed was assessed using the trail making test , part a ( tmt - a , z - score ) .", "attentional set - shifting was measured using the trail making test , part b ( tmt - b , z - score ) .", "working memory was assessed using the digit span forward and backward subtest of the wechsler memory scale - iii ( raw scores ) .", "language was assessed with semantic and phonemic verbal fluency via the controlled oral word associated test ( cowat animals and letters , z - score ) .", "the ability to retain learned verbal memory was assessed using the logical memory subtest from the wechsler memory scale - iii ( lm - i z - score , lm - ii z - score , % lm retention z - score ) . the mini - mental state examination ( mmse )", "demographic , clinical , and neuropsychological variables were compared between the two groups with the independent t - test or mann  whitney u test , depending on whether the variable met parametric assumptions .", "chi - square tests were used to examine gender and symptom laterality differences between groups .", "all analyses employed an alpha level of p < 0.05 and were two - tailed .", "spearman correlations were performed separately in each group to examine associations between anxiety and/or depression ratings and cognitive functions .", "as expected , the pda+ group reported significant greater levels of anxiety on the hads - a ( u = 0 , p < 0.001 ) and higher total score on the hads ( u = 1 , p < 0.001 ) compared to the pda group ( table 1 ) .", "groups were matched in age ( t(48 ) = 1.31 , p = 0.20 ) , disease duration ( u = 259 , p = 0.66 ) , updrs - iii score ( u = 250.5 , p = 0.65 ) , h&y ( u = 245 , p = 0.43 ) , ledd ( u = 159.5 , p = 0.80 ) , and depression ( hads - d ) ( u = 190.5 , p = 0.06 ) .", "additionally , all groups were matched in the distribution of gender (  = 0.098 , p = 0.75 ) and side - affected (  = 0.765 , p = 0.38 ) .", "there were no group differences for tmt - a performance ( u = 256 , p = 0.62 ) ( table 2 ) ; however , the pda+ group had worse performance on the trail making test part b ( t(46 ) = 2.03 , p = 0.048 ) compared to the pda group ( figure 1 ) .", "the pda+ group also demonstrated significantly worse performance on the digit span forward subtest ( t(48 ) = 2.22 , p = 0.031 ) and backward subtest ( u = 190.5 , p = 0.016 ) compared to the pda group ( figures 2(a ) and 2(b ) ) .", "neither semantic verbal fluency ( t(47 ) = 0.70 , p = 0.49 ) nor phonemic verbal fluency ( t(47 ) = 0.39 , p = 0.70 ) differed between groups .", "logical memory i immediate recall test ( u = 176 , p = 0.059 ) showed a trend that the pda+ group had worse new verbal learning and immediate recall abilities than the pda group . however , logical memory ii test performance ( u = 219 , p = 0.204 ) and logical memory % retention ( u = 242.5 , p = 0.434 ) did not differ between groups .", "there were also no differences between groups in global cognition ( mmse ) ( u = 222.5 , p = 0.23 ) .", "participants were split into lpd and rpd , and then further group differences were examined between pda+ and pda. importantly , the groups remained matched in age , disease duration , updrs - iii , dde , h&y stage , and depression but remained significantly different on self - reported anxiety .", "lpda+ demonstrated worse performance on the digit span forward test ( t(19 ) = 2.29 , p = 0.033 ) compared to lpda , whereas rpda+ demonstrated worse performance on the digit span backward test ( u = 36.5 , p = 0.006 ) , lm - i immediate recall ( u = 37.5 , p = 0.008 ) , and lm - ii ( u = 45.0 , p = 0.021 ) but not lm % retention ( u = 75.5 , p = 0.39 ) compared to rpda.", "this study is the first to directly compare cognition between pd patients with and without anxiety .", "the findings confirmed our hypothesis that anxiety negatively influences attentional set - shifting and working memory in pd .", "more specifically , we found that pd patients with anxiety were more impaired on the trail making test part b which assessed attentional set - shifting , on both digit span tests which assessed working memory and attention , and to a lesser extent on the logical memory test which assessed memory and new verbal learning compared to pd patients without anxiety . taken together ,", "these findings suggest that anxiety in pd may reduce processing capacity and impair processing efficiency , especially in the central executive and attentional systems of working memory in a similar way as seen in young healthy adults [ 26 , 27 ] .", "although the neurobiology of anxiety in pd remains unknown , many researchers have postulated that anxiety disorders are related to neurochemical changes that occur during the early , premotor stages of pd - related degeneration [ 37 , 38 ] such as nigrostriatal dopamine depletion , as well as cell loss within serotonergic and noradrenergic brainstem nuclei ( i.e. , raphe nuclei and locus coeruleus , resp . , which provide massive inputs to corticolimbic regions ) . over time", ", chronic dysregulation of adrenocortical and catecholamine functions can lead to hippocampal damage as well as dysfunctional prefrontal neural circuitries [ 39 , 40 ] , which play a key role in memory and attention .", "recent functional neuroimaging work has suggested that enhanced hippocampal activation during executive functioning and working memory tasks may represent compensatory processes for impaired frontostriatal functions in pd patients compared to controls . therefore , chronic stress from anxiety ,", "for example , may disrupt compensatory processes in pd patients and explain the cognitive impairments specifically in working memory and attention seen in pd patients with anxiety .", "it has also been suggested that hyperactivation within the putamen may reflect a compensatory striatal mechanism to maintain normal working memory performance in pd patients ; however , losing this compensatory activation has been shown to contribute to poor working memory performance .", "anxiety in mild pd has been linked to reduced putamen dopamine uptake which becomes more extensive as the disease progresses .", "this further supports the notion that anxiety may disrupt compensatory striatal mechanisms as well , providing another possible explanation for the cognitive impairments observed in pd patients with anxiety in this study .", "noradrenergic and serotonergic systems should also be considered when trying to explain the mechanisms by which anxiety may influence cognition in pd . although these neurotransmitter systems are relatively understudied in pd cognition , treating the noradrenergic and serotonergic systems has shown beneficial effects on cognition in pd .", "selective serotonin reuptake inhibitor , citalopram , was shown to improve response inhibition deficits in pd , while noradrenaline reuptake blocker , atomoxetine , has been recently reported to have promising effects on cognition in pd [ 45 , 46 ] .", "overall , very few neuroimaging studies have been conducted in pd in order to understand the neural correlates of pd anxiety and its underlying neural pathology .", "future research should focus on relating anatomical changes and neurochemical changes to neural activation in order to gain a clearer understanding on how these pathologies affect anxiety in pd . to further understand how anxiety and cognitive dysfunction are related ,", "future research should focus on using advanced structural and function imaging techniques to explain both cognitive and neural breakdowns that are associated with anxiety in pd patients .", "research has indicated that those with amnestic mild cognitive impairment who have more neuropsychiatric symptoms have a greater risk of developing dementia compared to those with fewer neuropsychiatric symptoms .", "future studies should also examine whether treating neuropsychiatric symptoms might impact the progression of cognitive decline and improve cognitive impairments in pd patients .", "previous studies have used pd symptom laterality as a window to infer asymmetrical dysfunction of neural circuits .", "for example , lpd patients have greater inferred right hemisphere pathology , whereas rpd patients have greater inferred left hemisphere pathology .", "thus , cognitive domains predominantly subserved by the left hemisphere ( e.g. , verbally mediated tasks of executive function and verbal memory ) might be hypothesized to be more affected in rpd than lpd ; however , this remains controversial .", "it has also been suggested that since anxiety is a common feature of left hemisphere involvement [ 48 , 49 ] , cognitive domains subserved by the left hemisphere may also be more strongly related to anxiety .", "results from this study showed selective verbal memory deficits in rpd patients with anxiety compared to rpd without anxiety , whereas lpd patients with anxiety had greater attentional / working memory deficits compared to lpd without anxiety .", "although these results align with previous research , interpretations of these findings should be made with caution due to the small sample size in the lpd comparison specifically .", "recent work has suggested that the hads questionnaire may underestimate the burden of anxiety related symptomology and therefore be a less sensitive measure of anxiety in pd [ 30 , 50 ] . in addition , our small sample size also limited the statistical power for detecting significant findings .", "based on these limitations , our findings are likely conservative and underrepresent the true impact anxiety has on cognition in pd . additionally , the current study employed a very brief neuropsychological assessment including one or two tests for each cognitive domain .", "future studies are encouraged to collect a more complex and comprehensive battery from a larger sample of pd participants in order to better understand the role anxiety plays on cognition in pd .", "another limitation of this study was the absence of diagnostic interviews to characterize participants ' psychiatric symptoms and specify the type of anxiety disorders included in this study .", "future studies should perform diagnostic interviews with participants ( e.g. , using dsm - v criteria ) rather than relying on self - reported measures to group participants , in order to better understand whether the type of anxiety disorder ( e.g. , social anxiety , phobias , panic disorders , and generalized anxiety ) influences cognitive performance differently in pd .", "one advantage the hads questionnaire provided over other anxiety scales was that it assessed both anxiety and depression simultaneously and allowed us to control for coexisting depression .", "although there was a trend that the pda+ group self - reported higher levels of depression than the pda group , all participants included in the study scored < 6 on the depression subscale of the hads .", "controlling for depression while assessing anxiety has been identified as a key shortcoming in the majority of recent work .", "considering many previous studies have investigated the influence of depression on cognition in pd without accounting for the presence of anxiety and the inconsistent findings reported to date , we recommend that future research should try to disentangle the influence of anxiety versus depression on cognitive impairments in pd . considering the growing number of clinical trials for treating depression , there are few if any for the treatment of anxiety in pd .", "anxiety is a key contributor to decreased quality of life in pd and greatly requires better treatment options .", "moreover , anxiety has been suggested to play a key role in freezing of gait ( fog ) , which is also related to attentional set - shifting [ 52 , 53 ] .", "future research should examine the link between anxiety , set - shifting , and fog , in order to determine whether treating anxiety might be a potential therapy for improving fog ."], "abstract_text": ["<S> research on the implications of anxiety in parkinson 's disease ( pd ) has been neglected despite its prevalence in nearly 50% of patients and its negative impact on quality of life . </S>", "<S> previous reports have noted that neuropsychiatric symptoms impair cognitive performance in pd patients ; however , to date , no study has directly compared pd patients with and without anxiety to examine the impact of anxiety on cognitive impairments in pd . </S>", "<S> this study compared cognitive performance across 50 pd participants with and without anxiety ( 17 pda+ ; 33 pda ) , who underwent neurological and neuropsychological assessment . </S>", "<S> group performance was compared across the following cognitive domains : simple attention / visuomotor processing speed , executive function ( e.g. , set - shifting ) , working memory , language , and memory / new verbal learning . </S>", "<S> results showed that pda+ performed significantly worse on the digit span forward and backward test and part b of the trail making task ( tmt - b ) compared to the pda group . </S>", "<S> there were no group differences in verbal fluency , logical memory , or tmt - a performance . in conclusion , </S>", "<S> anxiety in pd has a measurable impact on working memory and attentional set - shifting . </S>"], "labels": null, "section_names": ["1. Introduction", "2. Methods", "3. Results", "4. Discussion"], "sections": [["anxiety affects quality of life in those living with parkinson 's disease ( pd ) more so than overall cognitive status , motor deficits , apathy , and depression [ 13 ] .", "although anxiety and depression are often related and coexist in pd patients , recent research suggests that anxiety rather than depression is the most prominent and prevalent mood disorder in pd [ 5 , 6 ] . yet ,", "our current understanding of anxiety and its impact on cognition in pd , as well as its neural basis and best treatment practices , remains meager and lags far behind that of depression .", "overall , neuropsychiatric symptoms in pd have been shown to be negatively associated with cognitive performance .", "for example , higher depression scores have been correlated with lower scores on the mini - mental state exam ( mmse ) [ 8 , 9 ] as well as tests of memory and executive functions ( e.g. , attention ) [ 1014 ] .", "likewise , apathy and anhedonia in pd patients have been associated with executive dysfunction [ 10 , 1523 ] .", "however , few studies have specifically investigated the relationship between anxiety and cognition in pd .", "one study showed a strong negative relationship between anxiety ( both state and trait ) and overall cognitive performance ( measured by the total of the repeatable battery for the assessment of neuropsychological status index ) within a sample of 27 pd patients .", "furthermore , trait anxiety was negatively associated with each of the cognitive domains assessed by the rbans ( i.e. , immediate memory , visuospatial construction , language , attention , and delayed memory ) .", "two further studies have examined whether anxiety differentially affects cognition in patients with left - sided dominant pd ( lpd ) versus right - sided dominant pd ( rpd ) ; however , their findings were inconsistent .", "the first study found that working memory performance was worse in lpd patients with anxiety compared to rpd patients with anxiety , whereas the second study reported that , in lpd , apathy but not anxiety was associated with performance on nonverbally mediated executive functions and visuospatial tasks ( e.g. , tmt - b , wms - iii spatial span ) , while in rpd , anxiety but not apathy significantly correlated with performance on verbally mediated tasks ( e.g. , clock reading test and boston naming test ) .", "furthermore , anxiety was significantly correlated with neuropsychological measures of attention and executive and visuospatial functions . taken together ,", "it is evident that there are limited and inconsistent findings describing the relationship between anxiety and cognition in pd and more specifically how anxiety might influence particular domains of cognition such as attention and memory and executive functioning .", "it is also striking that , to date , no study has examined the influence of anxiety on cognition in pd by directly comparing groups of pd patients with and without anxiety while excluding depression .", "given that research on healthy young adults suggests that anxiety reduces processing capacity and impairs processing efficiency , especially in the central executive and attentional systems of working memory [ 26 , 27 ] , we hypothesized that pd patients with anxiety would show impairments in attentional set - shifting and working memory compared to pd patients without anxiety .", "furthermore , since previous work , albeit limited , has focused on the influence of symptom laterality on anxiety and cognition , we also explored this relationship ."], ["seventeen pd patients with anxiety and thirty - three pd patients without anxiety were included in this study ( see table 1 ) .", "the cross - sectional data from these participants was taken from a patient database that has been compiled over the past 8 years ( since 2008 ) at the parkinson 's disease research clinic at the brain and mind centre , university of sydney .", "inclusion criteria involved a diagnosis of idiopathic pd according to the united kingdom parkinson 's disease society brain bank criteria   and were confirmed by a neurologist ( sjgl ) .", "patients also had to have an adequate proficiency in english and have completed a full neuropsychological assessment .", "ten patients in this study ( 5 pd with anxiety ; 5 pd without anxiety ) were taking psychotropic drugs ( i.e. , benzodiazepine or selective serotonin reuptake inhibitor ) .", "patients were also excluded if they had other neurological disorders , psychiatric disorders other than affective disorders ( such as anxiety ) , or if they reported a score greater than six on the depression subscale of the hospital anxiety and depression scale ( hads ) .", "thus , all participants who scored within a  depressed  ( hads - d > 6 ) range were excluded from this study , in attempt to examine a refined sample of pd patients with and without anxiety in order to determine the independent effect of anxiety on cognition .", "this research was approved by the human research ethics committee of the university of sydney , and written informed consent was obtained from all participants .", "self - reported hads was used to assess anxiety in pd and has been previously shown to be a useful measure of clinical anxiety in pd .", "a cut - off score of > 8 on the anxiety subscale of the hads ( hads - a ) was used to identify pd cases with anxiety ( pda+ ) , while a cut - off score of < 6 on the hads - a was used to identify pd cases without anxiety ( pda ) .", "this criterion was more stringent than usual ( > 7 cut - off score ) , in effort to create distinct patient groups .", "the neurological evaluation rated participants according to hoehn and yahr ( h&y ) stages   and assessed their motor symptoms using part iii of the revised mds task force unified parkinson 's disease rating scale ( updrs ) . in a similar way", "this was determined by calculating a total left and right score from rigidity items 3035 , voluntary movement items 3643 , and tremor items 5057 from the mds - updrs part iii ( see table 1 ) .", "processing speed was assessed using the trail making test , part a ( tmt - a , z - score ) .", "attentional set - shifting was measured using the trail making test , part b ( tmt - b , z - score ) .", "working memory was assessed using the digit span forward and backward subtest of the wechsler memory scale - iii ( raw scores ) .", "language was assessed with semantic and phonemic verbal fluency via the controlled oral word associated test ( cowat animals and letters , z - score ) .", "the ability to retain learned verbal memory was assessed using the logical memory subtest from the wechsler memory scale - iii ( lm - i z - score , lm - ii z - score , % lm retention z - score ) . the mini - mental state examination ( mmse )", "demographic , clinical , and neuropsychological variables were compared between the two groups with the independent t - test or mann  whitney u test , depending on whether the variable met parametric assumptions .", "chi - square tests were used to examine gender and symptom laterality differences between groups .", "all analyses employed an alpha level of p < 0.05 and were two - tailed .", "spearman correlations were performed separately in each group to examine associations between anxiety and/or depression ratings and cognitive functions ."], ["as expected , the pda+ group reported significant greater levels of anxiety on the hads - a ( u = 0 , p < 0.001 ) and higher total score on the hads ( u = 1 , p < 0.001 ) compared to the pda group ( table 1 ) .", "groups were matched in age ( t(48 ) = 1.31 , p = 0.20 ) , disease duration ( u = 259 , p = 0.66 ) , updrs - iii score ( u = 250.5 , p = 0.65 ) , h&y ( u = 245 , p = 0.43 ) , ledd ( u = 159.5 , p = 0.80 ) , and depression ( hads - d ) ( u = 190.5 , p = 0.06 ) .", "additionally , all groups were matched in the distribution of gender (  = 0.098 , p = 0.75 ) and side - affected (  = 0.765 , p = 0.38 ) .", "there were no group differences for tmt - a performance ( u = 256 , p = 0.62 ) ( table 2 ) ; however , the pda+ group had worse performance on the trail making test part b ( t(46 ) = 2.03 , p = 0.048 ) compared to the pda group ( figure 1 ) .", "the pda+ group also demonstrated significantly worse performance on the digit span forward subtest ( t(48 ) = 2.22 , p = 0.031 ) and backward subtest ( u = 190.5 , p = 0.016 ) compared to the pda group ( figures 2(a ) and 2(b ) ) .", "neither semantic verbal fluency ( t(47 ) = 0.70 , p = 0.49 ) nor phonemic verbal fluency ( t(47 ) = 0.39 , p = 0.70 ) differed between groups .", "logical memory i immediate recall test ( u = 176 , p = 0.059 ) showed a trend that the pda+ group had worse new verbal learning and immediate recall abilities than the pda group . however , logical memory ii test performance ( u = 219 , p = 0.204 ) and logical memory % retention ( u = 242.5 , p = 0.434 ) did not differ between groups .", "there were also no differences between groups in global cognition ( mmse ) ( u = 222.5 , p = 0.23 ) .", "participants were split into lpd and rpd , and then further group differences were examined between pda+ and pda. importantly , the groups remained matched in age , disease duration , updrs - iii , dde , h&y stage , and depression but remained significantly different on self - reported anxiety .", "lpda+ demonstrated worse performance on the digit span forward test ( t(19 ) = 2.29 , p = 0.033 ) compared to lpda , whereas rpda+ demonstrated worse performance on the digit span backward test ( u = 36.5 , p = 0.006 ) , lm - i immediate recall ( u = 37.5 , p = 0.008 ) , and lm - ii ( u = 45.0 , p = 0.021 ) but not lm % retention ( u = 75.5 , p = 0.39 ) compared to rpda."], ["this study is the first to directly compare cognition between pd patients with and without anxiety .", "the findings confirmed our hypothesis that anxiety negatively influences attentional set - shifting and working memory in pd .", "more specifically , we found that pd patients with anxiety were more impaired on the trail making test part b which assessed attentional set - shifting , on both digit span tests which assessed working memory and attention , and to a lesser extent on the logical memory test which assessed memory and new verbal learning compared to pd patients without anxiety . taken together ,", "these findings suggest that anxiety in pd may reduce processing capacity and impair processing efficiency , especially in the central executive and attentional systems of working memory in a similar way as seen in young healthy adults [ 26 , 27 ] .", "although the neurobiology of anxiety in pd remains unknown , many researchers have postulated that anxiety disorders are related to neurochemical changes that occur during the early , premotor stages of pd - related degeneration [ 37 , 38 ] such as nigrostriatal dopamine depletion , as well as cell loss within serotonergic and noradrenergic brainstem nuclei ( i.e. , raphe nuclei and locus coeruleus , resp . , which provide massive inputs to corticolimbic regions ) . over time", ", chronic dysregulation of adrenocortical and catecholamine functions can lead to hippocampal damage as well as dysfunctional prefrontal neural circuitries [ 39 , 40 ] , which play a key role in memory and attention .", "recent functional neuroimaging work has suggested that enhanced hippocampal activation during executive functioning and working memory tasks may represent compensatory processes for impaired frontostriatal functions in pd patients compared to controls . therefore , chronic stress from anxiety ,", "for example , may disrupt compensatory processes in pd patients and explain the cognitive impairments specifically in working memory and attention seen in pd patients with anxiety .", "it has also been suggested that hyperactivation within the putamen may reflect a compensatory striatal mechanism to maintain normal working memory performance in pd patients ; however , losing this compensatory activation has been shown to contribute to poor working memory performance .", "anxiety in mild pd has been linked to reduced putamen dopamine uptake which becomes more extensive as the disease progresses .", "this further supports the notion that anxiety may disrupt compensatory striatal mechanisms as well , providing another possible explanation for the cognitive impairments observed in pd patients with anxiety in this study .", "noradrenergic and serotonergic systems should also be considered when trying to explain the mechanisms by which anxiety may influence cognition in pd . although these neurotransmitter systems are relatively understudied in pd cognition , treating the noradrenergic and serotonergic systems has shown beneficial effects on cognition in pd .", "selective serotonin reuptake inhibitor , citalopram , was shown to improve response inhibition deficits in pd , while noradrenaline reuptake blocker , atomoxetine , has been recently reported to have promising effects on cognition in pd [ 45 , 46 ] .", "overall , very few neuroimaging studies have been conducted in pd in order to understand the neural correlates of pd anxiety and its underlying neural pathology .", "future research should focus on relating anatomical changes and neurochemical changes to neural activation in order to gain a clearer understanding on how these pathologies affect anxiety in pd . to further understand how anxiety and cognitive dysfunction are related ,", "future research should focus on using advanced structural and function imaging techniques to explain both cognitive and neural breakdowns that are associated with anxiety in pd patients .", "research has indicated that those with amnestic mild cognitive impairment who have more neuropsychiatric symptoms have a greater risk of developing dementia compared to those with fewer neuropsychiatric symptoms .", "future studies should also examine whether treating neuropsychiatric symptoms might impact the progression of cognitive decline and improve cognitive impairments in pd patients .", "previous studies have used pd symptom laterality as a window to infer asymmetrical dysfunction of neural circuits .", "for example , lpd patients have greater inferred right hemisphere pathology , whereas rpd patients have greater inferred left hemisphere pathology .", "thus , cognitive domains predominantly subserved by the left hemisphere ( e.g. , verbally mediated tasks of executive function and verbal memory ) might be hypothesized to be more affected in rpd than lpd ; however , this remains controversial .", "it has also been suggested that since anxiety is a common feature of left hemisphere involvement [ 48 , 49 ] , cognitive domains subserved by the left hemisphere may also be more strongly related to anxiety .", "results from this study showed selective verbal memory deficits in rpd patients with anxiety compared to rpd without anxiety , whereas lpd patients with anxiety had greater attentional / working memory deficits compared to lpd without anxiety .", "although these results align with previous research , interpretations of these findings should be made with caution due to the small sample size in the lpd comparison specifically .", "recent work has suggested that the hads questionnaire may underestimate the burden of anxiety related symptomology and therefore be a less sensitive measure of anxiety in pd [ 30 , 50 ] . in addition , our small sample size also limited the statistical power for detecting significant findings .", "based on these limitations , our findings are likely conservative and underrepresent the true impact anxiety has on cognition in pd . additionally , the current study employed a very brief neuropsychological assessment including one or two tests for each cognitive domain .", "future studies are encouraged to collect a more complex and comprehensive battery from a larger sample of pd participants in order to better understand the role anxiety plays on cognition in pd .", "another limitation of this study was the absence of diagnostic interviews to characterize participants ' psychiatric symptoms and specify the type of anxiety disorders included in this study .", "future studies should perform diagnostic interviews with participants ( e.g. , using dsm - v criteria ) rather than relying on self - reported measures to group participants , in order to better understand whether the type of anxiety disorder ( e.g. , social anxiety , phobias , panic disorders , and generalized anxiety ) influences cognitive performance differently in pd .", "one advantage the hads questionnaire provided over other anxiety scales was that it assessed both anxiety and depression simultaneously and allowed us to control for coexisting depression .", "although there was a trend that the pda+ group self - reported higher levels of depression than the pda group , all participants included in the study scored < 6 on the depression subscale of the hads .", "controlling for depression while assessing anxiety has been identified as a key shortcoming in the majority of recent work .", "considering many previous studies have investigated the influence of depression on cognition in pd without accounting for the presence of anxiety and the inconsistent findings reported to date , we recommend that future research should try to disentangle the influence of anxiety versus depression on cognitive impairments in pd . considering the growing number of clinical trials for treating depression , there are few if any for the treatment of anxiety in pd .", "anxiety is a key contributor to decreased quality of life in pd and greatly requires better treatment options .", "moreover , anxiety has been suggested to play a key role in freezing of gait ( fog ) , which is also related to attentional set - shifting [ 52 , 53 ] .", "future research should examine the link between anxiety , set - shifting , and fog , in order to determine whether treating anxiety might be a potential therapy for improving fog ."]]}
{"article_id": "PMC3309138", "article_text": ["small non - coding rnas are transcribed into mrna but remain untranslated in eukaryotic cells .", "they include sirna ( small interfering rna ) , mirna ( microrna ) , pirna ( piwi - interacting rna ) and snorna ( small nucleolar rna ) .", "mirnas are a class of multifunctional singled - stranded small rna which are ~20  nt in length and regulate the stability or translational efficiency of targeted messenger rna depending on the base - pairing complementarity between the mirna and its target mrna [ 1 , 2 ] . although over 1,000 mirna sequences have been identified from the tissues or cells of human origin and other species , as many as 1,000 to 10,000 mirnas per genome have been predicted [ 3 , 4 ] .", "mirnas regulate a broad range of biological processes including timing of development , cell cycle progression , stem cell self - renewal , differentiation , cancer initiation , cancer cell proliferation , metastasis and apoptosis [ 511 ] .", "cancer is caused by multiple processes including uncontrolled cellular proliferation and inappropriate survival of apoptotic cells .", "many regulatory factors switch on or off genes that govern cell division and direct cellular proliferation .", "mirnas regulate gene expression and play important roles in the onset and progression of tumorigenesis .", "emerging evidence demonstrates the involvement of mirna in mammary gland tumorigenesis , functioning either as tumor suppressors or oncogenes .", "although the current treatment of radiation therapy , chemotherapy and hormone therapy slow mammary gland tumor growth , prolong survival and improve the quality of patients life , metastatic breast cancer still remains incurable due to our limited understanding of the molecular mechanisms through which tumorigenesis and metastasis occur .", "as small non - coding rnas regulate gene expression and tumorigenesis , they may represent a novel cancer therapy .", "unlike mrna , mirnas are transcribed but never translated . some mirnas are transcribed from non - coding regions between genes , deriving from independent transcription unit .", "other mirnas are transcribed together with coding mrnas from the coding region of the genome , deriving from the introns of gene transcripts [ 13 , 14 ] .", "mirna gene copy number gain / loss and mirna gene mutation have been observed in breast cancer resulting in the aberrant expression of mirna .", "the first study about the altered expression of mirnas in human breast cancer patients and human breast cancer cell lines was reported in 2005 by lorio et al . ,", "in which 29 mirnas were identified with aberrant expression based on microarray and northern blot analysis of 76 breast tumor samples and 14 human breast cell lines .", "zhang and colleagues analyzed 283 human mirna genes on 55 human breast primary tumors and 18 human breast cancer cell lines using array - based comparative genomic hybridization .", "the results demonstrated a high frequency ( ~72.8% ) of gene copy number abnormality in mirna - containing regions in human breast cancer .", "wang et al . collected 68 patients with newly diagnosed breast cancer and examined the expression of selected mirnas in tumor and adjacent non - tumor tissues .", "mir-21 , mir-106a and mir-155 were significantly over - expressed in the tumor specimens compared with normal controls , whereas mir-126 , mir-199a and mir-335 were significantly decreased in expression in the tumor samples .", "our studies of the mir-17 - 92 cluster demonstrated decreased expression of mir-17/20 in human breast cancer specimens compared with matching normal breast tissue from the same patient .", "subsequent analysis identified reduced mir-17/20 expression in node - positive compared with node - negative breast cancers and demonstrated that mir-17/20 inhibited breast cancer cell migration and invasion via a heterotypic signaling .", "although the tendency for a global decrease of mirna expression in human cancers originally suggested a general tumor suppressor function of mirnas , subsequent studies showing the aberrant expression of specific mirnas in breast cancer suggest mirna - specific roles in breast cancer onset and progression .", "many distinct mirnas have been shown to regulate breast cancer cell proliferation , apoptosis , cancer stem cell expansion , and tumorigenesis .", "mirna may function as either tumor suppressors or oncogenes depending on the cell type , culture conditions , target genes and pathway .", "the involvement of mirna in mammary gland tumorigenesis has been reviewed recently [ 21 , 22 ] .", "le et al . described the expression pattern and regulatory network of key mirnas in breast cancer , including let-7 , mir-34 , mir-125 , mir-200 family , mir-205 , mir-21 , mir-10 and the mir-17 - 92 cluster .", "adams et al . reviewed the mirna regulation of estrogen signaling pathway and erbb2/her signaling pathway in breast cancer .", "the understanding of how mirnas are involved in breast cancer through regulating the cell cycle remains rudimentary .", "herein we summarize the recent literature and research progress on the mechanism by which mirnas regulate the breast cancer cell cycle and cellular proliferation ( fig . ", "1mirna regulation of mammary gland tumorigenesis in control of the cell cycle . through targeting different genes and different cyclin / cdk complexes , mir-17/20 and", "let-7 regulate the g1-s transition ; mir-21 and mir-27a regulate the g2-m checkpoint mirna regulation of mammary gland tumorigenesis in control of the cell cycle . through targeting different genes and different cyclin / cdk complexes , mir-17/20 and", "let-7 regulate the g1-s transition ; mir-21 and mir-27a regulate the g2-m checkpoint cyclin d1 is either overexpressed or amplified in ~50% of breast cancer .", "the abundance of cyclin d1 is rate - limiting in breast cancer cellular proliferation and g1-s phase transition [ 23 , 24 ] .", "in addition , cyclin d1 is a critical downstream target of erbb2- , ras- and -catenin- induced breast cancers , and is sufficient for the induction of mammary tumors when targeted to the mammary gland of mice .", "antisense inhibition of cyclin d1 expression in vivo suppressed the growth of neut - transformed mammary adenocarcinoma cells in nude mice .", "conserved sequences of the cyclin d1 3utr contain potential binding sites for multiple mirnas including mir-17/20/106 , mir-15/16 , mir-23 and let-7 .", "mir-17/20 binds the cyclin d1 3utr , inhibiting the expression of cyclin d1 , resulting in cell cycle arrest at the g1 phase and suppression of mcf-7 cell proliferation [ 18 , 26 ] .", "the regulation of cyclin d1 expression by mir-17 - 92 , as well as mir-15/16 , was confirmed by deshpande et al . .", "the let-7 family functions as a tumor suppressor in a variety of cancers including lung , colon , ovarian   and breast cancer .", "schultz et al . demonstrated the downregulation of cyclin d1 by mirna let-7 in control of cancer cell growth .", "the regulation of cyclin d1 by mirna is likely of broad importance as cyclin d1 encodes the regulatory subunit of a kinase that phosphorylates and inactivates the prb family proteins to inhibit dna synthesis , and phosphorylates nuclear respiratory factor 1 ( nrf-1 ) to inhibit mitochondria biogenesis [ 32 , 33 ] .", "furthermore , cyclin d1 promotes breast epithelial cell angiogenesis and migration , and promotes chromosomal instability which in turn contributes to tumorigenesis .", "the mir-221/222 cluster regulates the cell cycle , cell growth and epithelial - to - mesenchymal transition ( emt ) in breast cancer .", "mir-221/222 inhibited p27 and p57 abundance , facilitating g1-s phase transition , thereby promoting cancer cell proliferation [ 36 , 37 ] .", "moreover , mir-221/222 may contribute to the aggressive clinical behavior of basal - like breast cancers .", "the breast cancer basal - like subtype - specific mirnas , mir-221 and mir-222 , promote emt in breast cancer by targeting trps1 ( trichorhinophalangeal syndrome type 1 ) which inhibits emt by repressing zeb2 expression .", "mir-221 and/or mir-222 expression in mcf-7 and t47d breast cancer cells decreased er expression associated with tamoxifen resistance .", "the onco - mirna mir-21 is overexpressed in a wide variety of cancers including breast cancer [ 40 , 41 ] .", "mir-21 induced cellular proliferation , migration , invasion , emt , cancer stem cell characteristics and chemotherapy resistance in human breast cancer [ 42 , 43 ] .", "high mir-21 level is associated with poor prognosis , advanced stage , positive lymph node status and reduced survival time in breast cancer .", "mir-21 promotes mcf-7 cellular proliferation in part through inhibiting the expression of a tumor suppressor gene programmed cell death 4 ( pdcd4 ) . in colon cancer ,", "mir-21 participates in a dna damage - induced g2-m checkpoint through suppressing the cell cycle regulator cdc25a .", "a recent report demonstrated the mir-21 regulates the cell cycle through targeting cdc25a in mcf-7 breast cancer cells . with a potential anti - cancer chemical 3,3-diindolylmethane treatment ,", "mir-27a expression is upregulated in human breast cancer cell lines . in mda - mb-231 cells ,", "mir-27a negatively regulated the zinc finger zbtb10 gene and myt-1 , thereby promoting breast cancer cell proliferation .", "mir-27a suppressed myt-1 , increased cdc2/cyclin b activity and promoted the g2-m checkpoint in mda - mb-231 cells . thus , distinct mirnas affect key genetic targets that govern distinct cell - cycle checkpoints including cyclins , cdks , cdk inhibitors and the g2-m regulation apparatus .", "in addition to cell - cycle control , breast tumor onset and progression and breast tumor stem cells are also regulated by distinct mirnas .", "cancer stem cells ( cscs ) are characterized by their self - renewal capacity , an ability to differentiate into non - tumorigenic cell progeny , and their ability to seed tumors when transplanted into animal hosts .", "cell surface markers such as cd44 , cd24 , cd133 , epithelial - specific antigen and aldehyde dehydrogenase-1 are frequently used to isolate and enrich cscs .", "the involvement of mirnas in regulating tumor formation by cscs or tumor - initiating cells ( t - ic ) has been widely investigated .", "let-7 expression is very low to undetectable level in embryonic stem cells ( es cells ) and increases with differentiation .", "a comparison of mirna expression between breast t - ic and non - t - ic demonstrated reduced let-7 expression in t - ic and increased abundance with differentiation .", "transduction of breast cscs with let-7 reduced the proportion of undifferentiated cells , inhibited cell proliferation , mammosphere formation , and tumor formation in vivo .", "clarke and colleagues identified 37 mirnas which were differentially expressed between human breast cscs ( cd44cd24lineage ) and lineage nontumorigenic breast cancer cells .", "the mir-200 family members were downregulated in human breast cscs and normal mammary stem / progenitor cells .", "expression of mir-200 inhibited breast cancer stem cell expansion in vitro , and suppressed the tumor formation ability of human breast cancer stem cell in vivo .", "ectopic mir-34c expression reduced breast t - ics self - renewal , inhibited emt and suppressed tumor cell invasiveness via silencing notch4 .", "zhu et al . found the reduced mir-128 expression in human breast t - ic was accompanied by bmi-1 and abcc5 overexpression , and associated with chemotherapeutic resistance and poor survival .", "enforced mir-128 expression increased the sensitivity of breast cancer cells to doxorubicin - induced apoptosis and dna damage .", "emerging evidence has demonstrated the importance of cscs in cancer initiation , cancer metastasis and drug resistance .", "cscs are believed to be one of the most promising targets for cure of cancer .", "the discovery that non - coding rnas regulate cscs widens our understanding of cscs , and may provide potential novel strategies for breast cancer therapy .", "deletion of chromosome 6q , including region 6q14-q16 , is frequently observed in breast cancer .", "the small non - coding snorna u50 is a candidate tumor suppressor gene in the 6q14 - 16 region , playing a role in the development and/or progression of breast cancer .", "genomic deletion and transcriptional downregulation of snorna u50 was detected in breast cancer cell lines .", "re - expression of snorna u50 inhibited colony formation of the human breast cancer cells hs578 t and mda - mb-231 .", "pirnas are small non - coding rna that form rna - protein complexes through interactions with piwi proteins .", "pirna was initially discovered in germ line cells , and considered as germ line - specific small rnas .", "emerging evidence indicates that pirna expression occurs in somatic cells [ 57 , 58 ] and piwil2 expression has been identified in human breast cancer cells .", "high - throughput deep sequencing identified a group of small rnas matching pirna sequences in human breast cancer tissues and breast cancer cell lines .", "the study of these non - coding small rnas in human cancer is just starting .", "the identification of the expression signature of these non - coding small rnas in breast cancer subtypes , and an understanding of their functional significance to oncogene expression , tumor initiation and tumor cell metastasis may shed important new perspectives on the role of these non - coding small rnas in breast cancer .", "small non - coding rna - based diagnostic and therapeutic applications for human cancer are expected in the near future . although tumor - targeted delivery and local administration are still major challenges to the practical application of gene therapy for cancer , mirna - based cancer therapeutic approaches are being established and tested in animal models .", "synthetic mirna mimics or mirna expression vectors have been successfully applied to restore or overexpress mirna in vitro . chemically modified lna anti - sense mirna inhibitor and other approaches have been used to block mirna function in cells .", "kim et al . recently reported significant anti - tumor effect of virus - mediated delivery of mir-145 combined with 5-fu to treat breast cancer .", "intranasal delivery of let-7   and intravenous delivery of mir-34a mimics   for non - small - cell lung cancer treatment and a virus - mediated delivery of mir-26a for liver cancer treatment in mouse model   demonstrate the promise of mirna for treatment of cancer .", "dysregulated expression of mirnas has implicated components of the non - coding genome as either oncogenes or tumor suppressors of breast cancer .", "experimental evidence has shown specific mirnas regulating the initiation , progression , metastasis and drug resistance of breast cancer via control of the cell cycle , altering cellular proliferation , altering cellular apoptosis and/or controlling the population of tumor stem cells . dysregulated", "mirna expression has also been observed in cancer associated fibroblasts ( caf ) and in the systemic circulation [ 65 , 66 ] .", "the circulating mirnas have the potential to serve as novel diagnostic and prognostic biomarkers for breast cancer .", "a specific subset of dysregulated mirnas in breast cancer cells may serve as targets for gene therapy either alone or as an adjuvant treatment to current clinical protocols for breast cancer patients ."], "abstract_text": ["<S> small non - coding rnas include sirna , mirna , pirna and snorna . </S>", "<S> the involvement of mirnas in the regulation of mammary gland tumorigenesis has been widely studied while the role for other small non - coding rnas remains unclear . here </S>", "<S> we summarize the involvement of mirna in breast cancer onset and progression through regulating the cell cycle and cellular proliferation . </S>", "<S> the regulation of breast cancer stem cells and tumor regeneration by mirna is reviewed . </S>", "<S> in addition , the emerging evidence demonstrating the involvement of pirna and snorna in breast cancer is briefly described . </S>"], "labels": null, "section_names": ["Introduction", "Aberrant Expression of miRNA in Breast Cancer", "miRNA Regulation of Cell Cycle and Mammary Gland Tumorigenesis", "miRNA Regulation of Breast Cancer Stem Cells", "Other Non-coding Small RNAs in Breast Cancer", "Therapeutic Application of miRNA", "Concluding Remarks"], "sections": [["small non - coding rnas are transcribed into mrna but remain untranslated in eukaryotic cells .", "they include sirna ( small interfering rna ) , mirna ( microrna ) , pirna ( piwi - interacting rna ) and snorna ( small nucleolar rna ) .", "mirnas are a class of multifunctional singled - stranded small rna which are ~20  nt in length and regulate the stability or translational efficiency of targeted messenger rna depending on the base - pairing complementarity between the mirna and its target mrna [ 1 , 2 ] . although over 1,000 mirna sequences have been identified from the tissues or cells of human origin and other species , as many as 1,000 to 10,000 mirnas per genome have been predicted [ 3 , 4 ] .", "mirnas regulate a broad range of biological processes including timing of development , cell cycle progression , stem cell self - renewal , differentiation , cancer initiation , cancer cell proliferation , metastasis and apoptosis [ 511 ] .", "cancer is caused by multiple processes including uncontrolled cellular proliferation and inappropriate survival of apoptotic cells .", "many regulatory factors switch on or off genes that govern cell division and direct cellular proliferation .", "mirnas regulate gene expression and play important roles in the onset and progression of tumorigenesis .", "emerging evidence demonstrates the involvement of mirna in mammary gland tumorigenesis , functioning either as tumor suppressors or oncogenes .", "although the current treatment of radiation therapy , chemotherapy and hormone therapy slow mammary gland tumor growth , prolong survival and improve the quality of patients life , metastatic breast cancer still remains incurable due to our limited understanding of the molecular mechanisms through which tumorigenesis and metastasis occur .", "as small non - coding rnas regulate gene expression and tumorigenesis , they may represent a novel cancer therapy ."], ["unlike mrna , mirnas are transcribed but never translated . some mirnas are transcribed from non - coding regions between genes , deriving from independent transcription unit .", "other mirnas are transcribed together with coding mrnas from the coding region of the genome , deriving from the introns of gene transcripts [ 13 , 14 ] .", "mirna gene copy number gain / loss and mirna gene mutation have been observed in breast cancer resulting in the aberrant expression of mirna .", "the first study about the altered expression of mirnas in human breast cancer patients and human breast cancer cell lines was reported in 2005 by lorio et al . ,", "in which 29 mirnas were identified with aberrant expression based on microarray and northern blot analysis of 76 breast tumor samples and 14 human breast cell lines .", "zhang and colleagues analyzed 283 human mirna genes on 55 human breast primary tumors and 18 human breast cancer cell lines using array - based comparative genomic hybridization .", "the results demonstrated a high frequency ( ~72.8% ) of gene copy number abnormality in mirna - containing regions in human breast cancer .", "wang et al . collected 68 patients with newly diagnosed breast cancer and examined the expression of selected mirnas in tumor and adjacent non - tumor tissues .", "mir-21 , mir-106a and mir-155 were significantly over - expressed in the tumor specimens compared with normal controls , whereas mir-126 , mir-199a and mir-335 were significantly decreased in expression in the tumor samples .", "our studies of the mir-17 - 92 cluster demonstrated decreased expression of mir-17/20 in human breast cancer specimens compared with matching normal breast tissue from the same patient .", "subsequent analysis identified reduced mir-17/20 expression in node - positive compared with node - negative breast cancers and demonstrated that mir-17/20 inhibited breast cancer cell migration and invasion via a heterotypic signaling .", "although the tendency for a global decrease of mirna expression in human cancers originally suggested a general tumor suppressor function of mirnas , subsequent studies showing the aberrant expression of specific mirnas in breast cancer suggest mirna - specific roles in breast cancer onset and progression ."], ["many distinct mirnas have been shown to regulate breast cancer cell proliferation , apoptosis , cancer stem cell expansion , and tumorigenesis .", "mirna may function as either tumor suppressors or oncogenes depending on the cell type , culture conditions , target genes and pathway .", "the involvement of mirna in mammary gland tumorigenesis has been reviewed recently [ 21 , 22 ] .", "le et al . described the expression pattern and regulatory network of key mirnas in breast cancer , including let-7 , mir-34 , mir-125 , mir-200 family , mir-205 , mir-21 , mir-10 and the mir-17 - 92 cluster .", "adams et al . reviewed the mirna regulation of estrogen signaling pathway and erbb2/her signaling pathway in breast cancer .", "the understanding of how mirnas are involved in breast cancer through regulating the cell cycle remains rudimentary .", "herein we summarize the recent literature and research progress on the mechanism by which mirnas regulate the breast cancer cell cycle and cellular proliferation ( fig . ", "1mirna regulation of mammary gland tumorigenesis in control of the cell cycle . through targeting different genes and different cyclin / cdk complexes , mir-17/20 and", "let-7 regulate the g1-s transition ; mir-21 and mir-27a regulate the g2-m checkpoint mirna regulation of mammary gland tumorigenesis in control of the cell cycle . through targeting different genes and different cyclin / cdk complexes , mir-17/20 and", "let-7 regulate the g1-s transition ; mir-21 and mir-27a regulate the g2-m checkpoint cyclin d1 is either overexpressed or amplified in ~50% of breast cancer .", "the abundance of cyclin d1 is rate - limiting in breast cancer cellular proliferation and g1-s phase transition [ 23 , 24 ] .", "in addition , cyclin d1 is a critical downstream target of erbb2- , ras- and -catenin- induced breast cancers , and is sufficient for the induction of mammary tumors when targeted to the mammary gland of mice .", "antisense inhibition of cyclin d1 expression in vivo suppressed the growth of neut - transformed mammary adenocarcinoma cells in nude mice .", "conserved sequences of the cyclin d1 3utr contain potential binding sites for multiple mirnas including mir-17/20/106 , mir-15/16 , mir-23 and let-7 .", "mir-17/20 binds the cyclin d1 3utr , inhibiting the expression of cyclin d1 , resulting in cell cycle arrest at the g1 phase and suppression of mcf-7 cell proliferation [ 18 , 26 ] .", "the regulation of cyclin d1 expression by mir-17 - 92 , as well as mir-15/16 , was confirmed by deshpande et al . .", "the let-7 family functions as a tumor suppressor in a variety of cancers including lung , colon , ovarian   and breast cancer .", "schultz et al . demonstrated the downregulation of cyclin d1 by mirna let-7 in control of cancer cell growth .", "the regulation of cyclin d1 by mirna is likely of broad importance as cyclin d1 encodes the regulatory subunit of a kinase that phosphorylates and inactivates the prb family proteins to inhibit dna synthesis , and phosphorylates nuclear respiratory factor 1 ( nrf-1 ) to inhibit mitochondria biogenesis [ 32 , 33 ] .", "furthermore , cyclin d1 promotes breast epithelial cell angiogenesis and migration , and promotes chromosomal instability which in turn contributes to tumorigenesis .", "the mir-221/222 cluster regulates the cell cycle , cell growth and epithelial - to - mesenchymal transition ( emt ) in breast cancer .", "mir-221/222 inhibited p27 and p57 abundance , facilitating g1-s phase transition , thereby promoting cancer cell proliferation [ 36 , 37 ] .", "moreover , mir-221/222 may contribute to the aggressive clinical behavior of basal - like breast cancers .", "the breast cancer basal - like subtype - specific mirnas , mir-221 and mir-222 , promote emt in breast cancer by targeting trps1 ( trichorhinophalangeal syndrome type 1 ) which inhibits emt by repressing zeb2 expression .", "mir-221 and/or mir-222 expression in mcf-7 and t47d breast cancer cells decreased er expression associated with tamoxifen resistance .", "the onco - mirna mir-21 is overexpressed in a wide variety of cancers including breast cancer [ 40 , 41 ] .", "mir-21 induced cellular proliferation , migration , invasion , emt , cancer stem cell characteristics and chemotherapy resistance in human breast cancer [ 42 , 43 ] .", "high mir-21 level is associated with poor prognosis , advanced stage , positive lymph node status and reduced survival time in breast cancer .", "mir-21 promotes mcf-7 cellular proliferation in part through inhibiting the expression of a tumor suppressor gene programmed cell death 4 ( pdcd4 ) . in colon cancer ,", "mir-21 participates in a dna damage - induced g2-m checkpoint through suppressing the cell cycle regulator cdc25a .", "a recent report demonstrated the mir-21 regulates the cell cycle through targeting cdc25a in mcf-7 breast cancer cells . with a potential anti - cancer chemical 3,3-diindolylmethane treatment ,", "mir-27a expression is upregulated in human breast cancer cell lines . in mda - mb-231 cells ,", "mir-27a negatively regulated the zinc finger zbtb10 gene and myt-1 , thereby promoting breast cancer cell proliferation .", "mir-27a suppressed myt-1 , increased cdc2/cyclin b activity and promoted the g2-m checkpoint in mda - mb-231 cells . thus , distinct mirnas affect key genetic targets that govern distinct cell - cycle checkpoints including cyclins , cdks , cdk inhibitors and the g2-m regulation apparatus .", "in addition to cell - cycle control , breast tumor onset and progression and breast tumor stem cells are also regulated by distinct mirnas ."], ["cancer stem cells ( cscs ) are characterized by their self - renewal capacity , an ability to differentiate into non - tumorigenic cell progeny , and their ability to seed tumors when transplanted into animal hosts .", "cell surface markers such as cd44 , cd24 , cd133 , epithelial - specific antigen and aldehyde dehydrogenase-1 are frequently used to isolate and enrich cscs .", "the involvement of mirnas in regulating tumor formation by cscs or tumor - initiating cells ( t - ic ) has been widely investigated .", "let-7 expression is very low to undetectable level in embryonic stem cells ( es cells ) and increases with differentiation .", "a comparison of mirna expression between breast t - ic and non - t - ic demonstrated reduced let-7 expression in t - ic and increased abundance with differentiation .", "transduction of breast cscs with let-7 reduced the proportion of undifferentiated cells , inhibited cell proliferation , mammosphere formation , and tumor formation in vivo .", "clarke and colleagues identified 37 mirnas which were differentially expressed between human breast cscs ( cd44cd24lineage ) and lineage nontumorigenic breast cancer cells .", "the mir-200 family members were downregulated in human breast cscs and normal mammary stem / progenitor cells .", "expression of mir-200 inhibited breast cancer stem cell expansion in vitro , and suppressed the tumor formation ability of human breast cancer stem cell in vivo .", "ectopic mir-34c expression reduced breast t - ics self - renewal , inhibited emt and suppressed tumor cell invasiveness via silencing notch4 .", "zhu et al . found the reduced mir-128 expression in human breast t - ic was accompanied by bmi-1 and abcc5 overexpression , and associated with chemotherapeutic resistance and poor survival .", "enforced mir-128 expression increased the sensitivity of breast cancer cells to doxorubicin - induced apoptosis and dna damage .", "emerging evidence has demonstrated the importance of cscs in cancer initiation , cancer metastasis and drug resistance .", "cscs are believed to be one of the most promising targets for cure of cancer .", "the discovery that non - coding rnas regulate cscs widens our understanding of cscs , and may provide potential novel strategies for breast cancer therapy ."], ["deletion of chromosome 6q , including region 6q14-q16 , is frequently observed in breast cancer .", "the small non - coding snorna u50 is a candidate tumor suppressor gene in the 6q14 - 16 region , playing a role in the development and/or progression of breast cancer .", "genomic deletion and transcriptional downregulation of snorna u50 was detected in breast cancer cell lines .", "re - expression of snorna u50 inhibited colony formation of the human breast cancer cells hs578 t and mda - mb-231 .", "pirnas are small non - coding rna that form rna - protein complexes through interactions with piwi proteins .", "pirna was initially discovered in germ line cells , and considered as germ line - specific small rnas .", "emerging evidence indicates that pirna expression occurs in somatic cells [ 57 , 58 ] and piwil2 expression has been identified in human breast cancer cells .", "high - throughput deep sequencing identified a group of small rnas matching pirna sequences in human breast cancer tissues and breast cancer cell lines .", "the study of these non - coding small rnas in human cancer is just starting .", "the identification of the expression signature of these non - coding small rnas in breast cancer subtypes , and an understanding of their functional significance to oncogene expression , tumor initiation and tumor cell metastasis may shed important new perspectives on the role of these non - coding small rnas in breast cancer ."], ["small non - coding rna - based diagnostic and therapeutic applications for human cancer are expected in the near future . although tumor - targeted delivery and local administration are still major challenges to the practical application of gene therapy for cancer , mirna - based cancer therapeutic approaches are being established and tested in animal models .", "synthetic mirna mimics or mirna expression vectors have been successfully applied to restore or overexpress mirna in vitro . chemically modified lna anti - sense mirna inhibitor and other approaches have been used to block mirna function in cells .", "kim et al . recently reported significant anti - tumor effect of virus - mediated delivery of mir-145 combined with 5-fu to treat breast cancer .", "intranasal delivery of let-7   and intravenous delivery of mir-34a mimics   for non - small - cell lung cancer treatment and a virus - mediated delivery of mir-26a for liver cancer treatment in mouse model   demonstrate the promise of mirna for treatment of cancer ."], ["dysregulated expression of mirnas has implicated components of the non - coding genome as either oncogenes or tumor suppressors of breast cancer .", "experimental evidence has shown specific mirnas regulating the initiation , progression , metastasis and drug resistance of breast cancer via control of the cell cycle , altering cellular proliferation , altering cellular apoptosis and/or controlling the population of tumor stem cells . dysregulated", "mirna expression has also been observed in cancer associated fibroblasts ( caf ) and in the systemic circulation [ 65 , 66 ] .", "the circulating mirnas have the potential to serve as novel diagnostic and prognostic biomarkers for breast cancer .", "a specific subset of dysregulated mirnas in breast cancer cells may serve as targets for gene therapy either alone or as an adjuvant treatment to current clinical protocols for breast cancer patients ."]]}
