Coordinate Regulation of FOXO1 by miR-27a, miR-96, and miR-182 in Breast Cancer Cells

The FOXO1 transcription factor orchestrates the regulation of genes involved in the apoptotic response, cell cycle checkpoints, and cellular metabolism. FOXO1 is a putative tumor suppressor, and the expression of this gene is dysregulated in some cancers, including prostate and endometrial cancers. However, the molecular mechanism resulting in aberrant expression of human FOXO1 in cancer cells is poorly understood. We show here that FOXO1 mRNA is down-regulated in breast tumor samples as compared with normal breast tissue. Silencing of the microRNA processing enzymes, Drosha and Dicer, led to an increase in FOXO1 expression. We also identified functional and specific microRNA target sites in the FOXO1 3′-untranslated region for miR-27a, miR-96, and miR-182, microRNAs that have previously been linked to oncogenic transformation. The three microRNAs, miR-27a, miR-96 and miR-182, were observed to be highly expressed in MCF-7 breast cancer cells, in which the level of FOXO1 protein is very low. Antisense inhibitors to each of these microRNAs led to a significant increase in endogenous FOXO1 expression and to a decrease in cell number in a manner that was blocked by FOXO1 siRNA. Overexpression of FOXO1 resulted in decreased cell viability because of inhibition of cell cycle traverse and induction of cell death. We have identified a novel mechanism of FOXO1 regulation, and targeting of FOXO1 by microRNAs may contribute to transformation or maintenance of an oncogenic state in breast cancer cells. The FOXO1 transcription factor orchestrates the regulation of genes involved in the apoptotic response, cell cycle checkpoints, and cellular metabolism. FOXO1 is a putative tumor suppressor, and the expression of this gene is dysregulated in some cancers, including prostate and endometrial cancers. However, the molecular mechanism resulting in aberrant expression of human FOXO1 in cancer cells is poorly understood. We show here that FOXO1 mRNA is down-regulated in breast tumor samples as compared with normal breast tissue. Silencing of the microRNA processing enzymes, Drosha and Dicer, led to an increase in FOXO1 expression. We also identified functional and specific microRNA target sites in the FOXO1 3′-untranslated region for miR-27a, miR-96, and miR-182, microRNAs that have previously been linked to oncogenic transformation. The three microRNAs, miR-27a, miR-96 and miR-182, were observed to be highly expressed in MCF-7 breast cancer cells, in which the level of FOXO1 protein is very low. Antisense inhibitors to each of these microRNAs led to a significant increase in endogenous FOXO1 expression and to a decrease in cell number in a manner that was blocked by FOXO1 siRNA. Overexpression of FOXO1 resulted in decreased cell viability because of inhibition of cell cycle traverse and induction of cell death. We have identified a novel mechanism of FOXO1 regulation, and targeting of FOXO1 by microRNAs may contribute to transformation or maintenance of an oncogenic state in breast cancer cells. The Forkhead Box O subfamily of transcription factors (FOXO) regulates a variety of important cellular processes including metabolism, cellular differentiation, apoptosis, and cell-cycle progression (1.Gross D.N. van den Heuvel A.P. Birnbaum M.J. Oncogene. 2008; 27: 2320-2336Crossref PubMed Scopus (433) Google Scholar, 2.Fu Z. Tindall D.J. Oncogene. 2008; 27: 2312-2319Crossref PubMed Scopus (449) Google Scholar). Acting as master cellular regulators, FOXO transcription factors can both activate and repress target gene expression (3.Obsil T. Obsilova V. Oncogene. 2008; 27: 2263-2275Crossref PubMed Scopus (179) Google Scholar). The three predominant members of the FOXO family (FOXO1, FOXO3a, and FOXO4) were first implicated in tumorigenesis based on the observation that fusion proteins resulting from chromosomal breakpoints exist in certain types of cancers (2.Fu Z. Tindall D.J. Oncogene. 2008; 27: 2312-2319Crossref PubMed Scopus (449) Google Scholar). Recent evidence suggests that FOXO proteins function as tumor suppressors based on their role in regulating cell-cycle progression and inducing apoptosis (4.Paik J.H. Kollipara R. Chu G. Ji H. Xiao Y. Ding Z. Miao L. Tothova Z. Horner J.W. Carrasco D.R. Jiang S. Gilliland D.G. Chin L. Wong W.H. Castrillon D.H. DePinho R.A. Cell. 2007; 128: 309-323Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar). One regulatory mechanism of FOXO1 activity is through phosphorylation, primarily downstream of the insulin-stimulated phosphatidylinositol 3-kinase/AKT/protein kinase B signaling pathway, which results in nuclear exclusion (5.Rena G. Guo S. Cichy S.C. Unterman T.G. Cohen P. J. Biol. Chem. 1999; 274: 17179-17183Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar, 6.Guo S. Rena G. Cichy S. He X. Cohen P. Unterman T. J. Biol. Chem. 1999; 274: 17184-17192Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar, 7.Zhang X. Gan L. Pan H. Guo S. He X. Olson S.T. Mesecar A. Adam S. Unterman T.G. J. Biol. Chem. 2002; 277: 45276-45284Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar). FOXO1 activity can also be regulated by acetylation (8.Perrot V. Rechler M.M. Mol. Endocrinol. 2005; 19: 2283-2298Crossref PubMed Scopus (94) Google Scholar) and ubiquitination (9.Matsuzaki H. Daitoku H. Hatta M. Tanaka K. Fukamizu A. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 11285-11290Crossref PubMed Scopus (427) Google Scholar, 10.Huang H. Regan K.M. Wang F. Wang D. Smith D.I. van Deursen J.M. Tindall D.J. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 1649-1654Crossref PubMed Scopus (430) Google Scholar). In addition to insulin, FOXO1 can be down-regulated by other growth factors including estrogen (11.Mazumdar A. Kumar R. FEBS Lett. 2003; 535: 6-10Crossref PubMed Scopus (88) Google Scholar, 12.Lengyel F. Vértes Z. Kovács K.A. Környei J.L. Sümegi B. Vértes M. Steroids. 2007; 72: 422-428Crossref PubMed Scopus (23) Google Scholar) and epidermal growth factor (13.Jackson J.G. Kreisberg J.I. Koterba A.P. Yee D. Brattain M.G. Oncogene. 2000; 19: 4574-4581Crossref PubMed Scopus (77) Google Scholar). The estrogen receptor α also complexes with phosphorylated FOXO1 and mediates its export from the nucleus. These mitogens are important for the growth and survival of breast cancer cells and may contribute to maintaining low levels of FOXO1 in breast cancer cells. Although the activity of FOXO1 has been well characterized, very little is known about the regulation of FOXO1 expression, particularly in breast cancer. FOXO1 is down-regulated in several other cancers including endometrial carcinoma (14.Goto T. Takano M. Albergaria A. Briese J. Pomeranz K.M. Cloke B. Fusi L. Feroze-Zaidi F. Maywald N. Sajin M. Dina R.E. Ishihara O. Takeda S. Lam E.W. Bamberger A.M. Ghaem-Maghami S. Brosens J.J. Oncogene. 2008; 27: 9-19Crossref PubMed Scopus (85) Google Scholar) and ovarian cancer (15.Goto T. Takano M. Hirata J. Tsuda H. Br. J. Cancer. 2008; 98: 1068-1075Crossref PubMed Scopus (59) Google Scholar). In addition, restoration of FOXO1 expression in endometrial carcinoma cells decreases cellular proliferation (14.Goto T. Takano M. Albergaria A. Briese J. Pomeranz K.M. Cloke B. Fusi L. Feroze-Zaidi F. Maywald N. Sajin M. Dina R.E. Ishihara O. Takeda S. Lam E.W. Bamberger A.M. Ghaem-Maghami S. Brosens J.J. Oncogene. 2008; 27: 9-19Crossref PubMed Scopus (85) Google Scholar). Although the role of FOXO1 in tumorigenesis is not entirely clear, it has been hypothesized that the down-regulation of this gene is an important step in tumor formation. Recently, it was shown that FOXO1 is reduced in certain endometrial carcinoma cells lines as well as endometriod endometrial tumors (14.Goto T. Takano M. Albergaria A. Briese J. Pomeranz K.M. Cloke B. Fusi L. Feroze-Zaidi F. Maywald N. Sajin M. Dina R.E. Ishihara O. Takeda S. Lam E.W. Bamberger A.M. Ghaem-Maghami S. Brosens J.J. Oncogene. 2008; 27: 9-19Crossref PubMed Scopus (85) Google Scholar). Subsequent analysis suggested that the down-regulation of FOXO1 expression was because of a post-transcriptional mechanism (14.Goto T. Takano M. Albergaria A. Briese J. Pomeranz K.M. Cloke B. Fusi L. Feroze-Zaidi F. Maywald N. Sajin M. Dina R.E. Ishihara O. Takeda S. Lam E.W. Bamberger A.M. Ghaem-Maghami S. Brosens J.J. Oncogene. 2008; 27: 9-19Crossref PubMed Scopus (85) Google Scholar). A novel class of small RNA molecules, microRNAs, has been implicated in the post-transcriptional regulation of thousands of mRNA transcripts resulting in decreased protein expression of target genes (16.Bartel D.P. Cell. 2004; 116: 281-297Abstract Full Text Full Text PDF PubMed Scopus (29863) Google Scholar). are small RNA that gene expression by to the FOXO1 of a target mRNA resulting in of the or Recent have shown that microRNAs in to protein expression on a level D. J. D.P. 2008; PubMed Scopus Google Scholar, M. B. N. Z. R. N. 2008; PubMed Scopus Google Scholar). In addition, in microRNA genes a variety of as D.P. S. K.M. Xiao Y. A. D. D. J.L. M. N. G. A. K. 2007; PubMed Scopus Google Scholar, A. S. P. D.R. van S. D. K. G. M. A. 2007; PubMed Scopus Google Scholar) and X. J. Olson 2007; PubMed Scopus Google and these have the important role of these genes in and region small RNA normal FOXO1 show that FOXO1 expression is also down-regulated in breast tumor samples compared with normal breast tissue. We hypothesized that the low levels of FOXO1 are a of microRNA regulation, and identified three microRNAs that target FOXO1 miR-96, and and endogenous protein expression in MCF-7 breast cancer cells. of these microRNAs resulted in an increase in FOXO1 protein and in a decrease in cell number that was by FOXO1 siRNA. In addition, show that of FOXO1 in breast cancer cells resulted in decreased cell number both through inhibition of cell cycle traverse and cell death. has identified a novel mechanism for the down-regulation of FOXO1 in breast cancer and this may the transformation of breast cells and maintenance of an oncogenic and cells were through and cells were in with and cells were in with and were from and to the expression of of from samples from to breast tumor the with each of these samples can be on the The was a from of were with and were the and cells. were for and from was the and on a to the on the of the the of the FOXO1 from to in were and the for the were from and by The were with kinase and the the of endogenous FOXO1 were and the were by the endogenous microRNA The cell lines were with of the were for by the were by with in and for The was for and activity the were as to and is as mRNA transcripts were a RNA was the and of RNA was the was on in an with were the and are as the of three The for the and of microRNAs a transcription was from R. M. 2007; PubMed Scopus Google Scholar). were to the microRNA of The was by of of and for The was on first of and of were to a of and for and the was for was were as the addition of Subsequent were by of of and in a of were based on the of The was be that microRNAs expressed levels as of to were on a and with in expression was decreased microRNA or were in a of and MCF-7 cells the in cell were from the cell were a and samples were on an or (FOXO1, The protein was a blocked in in for were from and were with the the were with and with or both from expression was by and to from the of was to targeting Dicer, and were from and a of and or and MCF-7 cells were in and with the of or expression In some cells were with inhibitors to specific microRNAs or inhibitors targeting FOXO1 or the cells were and with and cells were for each viability is expressed as a of the or are expressed as the of cells of three MCF-7 cells were in a and with of or expression was to for was to the cells a of and was for were and in and and of was the were for each and the number of cells to the cell the of MCF-7 cells were on and with the was for cells were with and with in were blocked in normal and an was a of was a of were a with a were and the in analysis were expressed as the However, were as were an was FOXO3a, and mRNA expression was in human breast tumor samples from a of tumor as well as in normal breast samples by FOXO1 mRNA levels were decreased by about in tumor samples as compared with normal breast of and not the normal and tumor samples B and We on a of the levels of FOXO1 in breast tumors were in to post-transcriptional gene for FOXO1 post-transcriptional regulation in a of endometrial cancer. the FOXO1 a very which is a region that post-transcriptional regulation through several a of regulatory that a significant role in gene the that microRNAs target FOXO1 mRNA in breast of the microRNA were and FOXO1 levels were Drosha is a nuclear and is for the first step in microRNA from of Drosha reduced Drosha protein to levels and these to of Drosha FOXO1 mRNA and protein levels and A and the from the Drosha cells with to The Dicer, is for the step in microRNA processing that a microRNA from a of cells with mRNA levels by and by because is for its levels of low of was with an increase in endogenous FOXO1 mRNA and protein and These the that microRNAs a role or in the of FOXO1 expression in human breast cancers. In microRNAs with target sites the region of target The FOXO1 a very microRNA microRNA sites were in the FOXO1 target and and microRNA sites the FOXO1 mRNA these small of the FOXO1 were a that the FOXO1 was the of the and expression was compared with an in breast cancer cell MCF-7 and cells. The of the FOXO1 in from to were and several to of the microRNA miR-96, miR-182, and were to target the FOXO1 in and and these microRNAs were for of these microRNAs are to target miR-96, miR-182, and However, the regulation of these was not in this as the mRNA levels of these transcripts not in normal tumor breast tissue. A a target to the microRNA of a was to the endogenous activity of the The of a microRNA to the target in decreased activity because of the of microRNAs in cellular of the microRNAs, as by the significant activity in MCF-7 miR-96 and the of these were that a in the region of the target and In each the the be that miR-96 and in their may not activity in MCF-7 cells, it was not on and that it with the in FOXO1 mRNA regulated FOXO1 protein expression. on miR-27a, miR-96, and of microRNA target sites in the FOXO1 in MCF-7 cells. of the FOXO1 microRNA sites were and a to and to of the FOXO1 was with activity and to of and by with or a for of and by with miR-96 or a for and were the of the The and was with inhibitors the microRNAs or a the of three for sites the target and endogenous was the and for each was with activity and to activity for the the endogenous or the with the microRNA the of three for endogenous or In addition to the activity of the microRNAs, the expression levels of the three microRNAs, miR-27a, miR-96 and miR-182, were specific transcription were for each and was of miR-27a, miR-96, and was in breast cancer cell lines and three microRNAs levels in the MCF-7 cells. We also FOXO1 mRNA and protein levels in the cell Although levels are MCF-7 cells a FOXO1 mRNA and protein levels mRNA as the mechanism of microRNA on MCF-7 cells to putative microRNA target sites and the of of endogenous microRNA levels on FOXO1 expression. previously and of the FOXO1 each for miR-27a, miR-96, and each or was MCF-7 cells or with inhibitors to miR-96, or A was as a of of the FOXO1 a was In the of inhibitors or miR-182, this was be that to miR-96 not the from These that the of endogenous FOXO1 is because of the activity of microRNAs, particularly and gene expression and microRNAs may on a the of microRNA sites in the FOXO1 a a target both and was both sites were a each the microRNAs these inhibitors the microRNAs an were with the and activity was in MCF-7 cells. miR-27a, miR-182, miR-96, that these microRNAs are for the observed of was by of the endogenous or sites the sites of activity of the endogenous or the endogenous was of activity in MCF-7 cells. the role of microRNA regulation on endogenous FOXO1 protein expression, inhibitors or miR-96 and were MCF-7 cells and levels of FOXO1 protein were by a were as a of the microRNAs was analysis A and FOXO1 protein levels were by to in a manner of miR-27a, miR-96, and miR-182, that these microRNAs the expression of endogenous of of FOXO1 protein These the that FOXO1 expression is the post-transcriptional level by or A in MCF-7 cells that of FOXO1 decreased cell number and R.E. J.H. Z. Yee D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In this cell also and as of cell cycle and cell in breast cancer cells MCF-7 cells very low levels of FOXO1 were with FOXO1 or a FOXO1 that be phosphorylated and to the nucleus. Overexpression of FOXO1 was by analysis In addition, of the FOXO1 expression were with not not Overexpression of FOXO1 protein was in MCF-7 cells with a FOXO1 or the Overexpression of the FOXO1 resulted in protein primarily to the from the protein primarily to the nucleus. of the was also by the regulation of known downstream of FOXO1 and by and FOXO1 a functional MCF-7 cell viability was by MCF-7 cells were in and with of FOXO1 or were and with and cells were in of FOXO1 resulted in a decrease in cell viability A was observed with of the FOXO1 which resulted in a decrease in cell viability a decrease The of cells for each was to the number of cells with of these was to the of FOXO1 on cell MCF-7 cells were with FOXO1 or FOXO1 and the of cells was MCF-7 cells FOXO1 decrease in cells the FOXO1 protein an decrease in cell the observed decrease in cell viability was also because of the induction of apoptosis, expression was of FOXO1 in MCF-7 cells A significant increase in was observed of FOXO1 or and of these was in these of were as a and of These results show that the restoration of FOXO1 in MCF-7 breast cancer cells results in reduced cell number because of a decrease in proliferation and induction of is a FOXO1 is the down-regulation of miR-27a, miR-96, or reduced cell number in a manner that be by to inhibitors miR-27a, miR-96, or miR-182, not endogenous FOXO1 protein levels in MCF-7 cells and this was with a in cell number by to with FOXO1 not the of the inhibitors miR-27a, miR-96, and These evidence that the specific of FOXO1 to the of these three microRNAs in MCF-7 cells. The FOXO gene family transcription factors that of cell cycle traverse and to breast it also be that FOXO1 with estrogen receptor α and its A that the of FOXO1 in MCF-7 cells resulted in decreased cell number and R.E. J.H. Z. Yee D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In the these by that of FOXO1 proliferation and cell in breast cancer MCF-7 cells. The of cell cycle and of apoptosis a role in the of and in FOXO1 expression activity contribute to tumor Although have the by which FOXO1 protein activity and have been little is known about the regulation of FOXO1 expression The levels of FOXO1 proteins are in a variety of cancers, including prostate and endometrial carcinoma (14.Goto T. Takano M. Albergaria A. Briese J. Pomeranz K.M. Cloke B. Fusi L. Feroze-Zaidi F. Maywald N. Sajin M. Dina R.E. Ishihara O. Takeda S. Lam E.W. Bamberger A.M. Ghaem-Maghami S. Brosens J.J. Oncogene. 2008; 27: 9-19Crossref PubMed Scopus (85) Google Scholar, X. Guo P. Wang PubMed Scopus Google Scholar, R. S. H. A. 2007; PubMed Scopus Google Scholar, J. L. J. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). (14.Goto T. Takano M. Albergaria A. Briese J. Pomeranz K.M. Cloke B. Fusi L. Feroze-Zaidi F. Maywald N. Sajin M. Dina R.E. Ishihara O. Takeda S. Lam E.W. Bamberger A.M. Ghaem-Maghami S. Brosens J.J. Oncogene. 2008; 27: 9-19Crossref PubMed Scopus (85) Google Scholar) that FOXO1 mRNA is in endometriod endometrial tumors compared with normal also the mRNA levels of the other expressed FOXO family and and that the levels of these endometrial tumors and normal tissue. in this have shown that FOXO1 mRNA is also down-regulated in breast tumor samples compared with normal breast tissue. In the expression of the other FOXO family members and FOXO4) that are expressed in breast not normal and tumor breast tissue. and expression may in to specific has been shown to in MCF-7 cells, resulting in the expression of the A. S. M. Brosens J.J. G. Lam E.W. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus (433) Google Scholar). The mechanism by which FOXO1 expression is in breast or other cancer has not been (14.Goto T. Takano M. Albergaria A. Briese J. Pomeranz K.M. Cloke B. Fusi L. Feroze-Zaidi F. Maywald N. Sajin M. Dina R.E. Ishihara O. Takeda S. Lam E.W. Bamberger A.M. Ghaem-Maghami S. Brosens J.J. Oncogene. 2008; 27: 9-19Crossref PubMed Scopus (85) Google Scholar) this in endometriod endometrial carcinoma endometrial carcinoma cell cells and cells. cells FOXO1 and these were not by The also that the low levels of FOXO1 in cells were not because of or a decrease in the of FOXO1 mRNA in each cell and that cells that expressed low levels of FOXO1 protein a of mRNA of compared with the cells of which levels of FOXO1 on this the that the down-regulation of FOXO1 in endometrial carcinoma cells was because of some of post-transcriptional One important of post-transcriptional regulation is the of mRNA transcripts by hypothesized that microRNAs may a role in maintaining low levels of FOXO1 in breast cancer cells. We the of microRNAs in three important in microRNA Drosha the microRNA from the the from the a from which is in the to repress the target mRNA In this the of Drosha or led to a increase in the FOXO1 mRNA and protein levels in the breast cancer cell evidence that microRNAs are important for the of endogenous FOXO1 expression in some of breast cancer not FOXO1 mRNA in a target of or evidence of putative microRNA target sites the FOXO1 mRNA In the human FOXO1 for microRNA target observed several of target some microRNAs expression and not sites are it was not to that some of these significant However, of these and a significant of and analysis of these sites led to the that miR-27a, miR-96, and were to target each miR-96 and are from the microRNA and have miR-96 and are to have and be to of their functional of target may in the of of the of miR-27a, miR-96, and levels and activity in breast cancer cell lines that MCF-7 cells the expression. this was with mRNA and protein analysis of these sites in the that inhibitors miR-27a, miR-182, or miR-96 blocked the of these be that in this was not to the level of the and this be because of of microRNA regulation of these We also observed both sites were as to that by each have the regulation of a mRNA by A. D. R. L. P. M. N. 2005; PubMed Scopus Google the that in a the that the gene was regulated by and analysis and a functional observed that the addition of each microRNA in cells was to protein expression of and repress activity of a the the of was observed the addition of three microRNAs the of regulation by microRNAs A. D. R. L. P. M. N. 2005; PubMed Scopus Google Scholar). In the also observed from sites by that the microRNAs identified endogenous FOXO1 expression. In MCF-7 cells with of it was shown that of miR-27a, miR-96, or miR-182, not the endogenous FOXO1 levels by Although has been shown to repress the expression of a specific microRNA the first evidence of the regulation of endogenous FOXO1 expression by specific microRNAs Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). to this was implicated in breast cancer as an oncogenic S. X. S. 2007; PubMed Scopus Google Scholar) that is highly expressed in breast cancer cells, and inhibition of this microRNA in cells decreased cell also that RNA decreased the of cells in and the of cells in the the that genes involved in regulating the of the cell cycle and target S. X. S. 2007; PubMed Scopus Google Scholar). In a S.C. PubMed Scopus Google Scholar) that a of the of decreases levels in breast cancer cells. was of microRNAs in cell carcinoma compared with normal F. M. M. P. D. M. F. R. 2007; PubMed Scopus Google Scholar) and as an in T. H. Y. M. X. Lett. PubMed Scopus Google Scholar). has also been linked to in which it the receptor J. J. G. J. Wang X. S. FEBS Lett. PubMed Scopus Google Scholar). These evidence that can as an oncogenic microRNA and of regulation of downstream of FOXO1 to the of in maintaining a state of cell Although miR-96 and have not been previously with to breast has shown that miR-96 and are dysregulated in human including a variety of cancers. K. J.H. T. P. A. 2008; PubMed Scopus Google Scholar) that miR-96 and are down-regulated in a of These microRNAs are in a gene miR-96, miR-182, and and this is in human R. J.M. H. H. G. M. R. M. G. 2008; PubMed Scopus Google Scholar) and cell lines D. S. L. X. S. J. A. D. D. J. P. N. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar). has also been shown that miR-96 and are in cancer X. R. R. N. A. A. M. J. Mol. Cancer. PubMed Scopus Google tumors and cell lines A. A. A. A. A. O. B. P. A. R. M. 2008; PubMed Scopus Google and cells X. A. L. L. O. B. G. A. J. A. A. M.J. P. J. F. Mol. 2008; PubMed Scopus Google Scholar). A in the of Overexpression of in cell lines resulted in oncogenic as growth and on as well as and in D. S. L. X. S. J. A. D. D. J. P. N. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar). this identified a FOXO family as a target of These and miR-96 as oncogenic microRNAs because of their in cancers and the observation that their identified target genes are involved in the regulation of cell proliferation and In this that of the three expressed FOXO family FOXO1 is down-regulated in breast cancer as compared with normal tissue. We also that FOXO1 expression is regulated by microRNAs miR-96, and that have previously been implicated in These microRNAs target of the to repress endogenous expression of of these microRNAs led to restoration of FOXO1 expression. The restoration of FOXO1 expression in MCF-7 cells resulted in reduced cell decreased cell cycle and cell death. was a FOXO1 protein was of FOXO1 restoration by blocked the of microRNA microRNA expression, FOXO1 expression, and cell proliferation These that targeting of miR-27a, miR-96, and with of microRNA and FOXO1 levels may be of in breast cancer. We the of FOXO1 and from G. Unterman of of with

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