Cooperation between Dmp1 Loss and Cyclin D1 Overexpression in Breast Cancer

Cyclin D1 is a component of the core cell-cycle machinery and is frequently overexpressed in breast cancer. It physically interacts with the tumor suppressor Dmp1 that attenuates the oncogenic signals from Ras and HER2 by inducing Arf/p53-dependent cell-cycle arrest. Currently, the biological significance of Dmp1–cyclin D1 interplay in breast cancer has not been determined. Here, we show that cyclin D1 bound to Dmp1 to activate both Arf and Ink4a promoters and, consequently, induced apoptosis or G2/M cell-cycle delay in normal cells to protect them from neoplastic transformation. The cyclin D1–induced Ink4a/Arf gene expression was dependent on Dmp1 because the induction was not detected in Dmp1-deficient or DMP1-depleted cells. Arf/Ink4a expression was increased in pre-malignant mammary glands from Dmp1+/+;MMTV-cyclin D1 and Dmp1+/+;MMTV-D1T286A mice but significantly down-regulated in those from Dmp1-deficient mice. Selective Dmp1 deletion was found in 21% of the MMTV-D1 and D1T286A mammary carcinomas, and the Dmp1 heterozygous status significantly accelerated mouse mammary tumorigenesis with reduced apoptosis and increased metastasis. Overall, our study reveals a pivotal role of combined Dmp1 loss and cyclin D1 overexpression in breast cancer. Cyclin D1 is a component of the core cell-cycle machinery and is frequently overexpressed in breast cancer. It physically interacts with the tumor suppressor Dmp1 that attenuates the oncogenic signals from Ras and HER2 by inducing Arf/p53-dependent cell-cycle arrest. Currently, the biological significance of Dmp1–cyclin D1 interplay in breast cancer has not been determined. Here, we show that cyclin D1 bound to Dmp1 to activate both Arf and Ink4a promoters and, consequently, induced apoptosis or G2/M cell-cycle delay in normal cells to protect them from neoplastic transformation. The cyclin D1–induced Ink4a/Arf gene expression was dependent on Dmp1 because the induction was not detected in Dmp1-deficient or DMP1-depleted cells. Arf/Ink4a expression was increased in pre-malignant mammary glands from Dmp1+/+;MMTV-cyclin D1 and Dmp1+/+;MMTV-D1T286A mice but significantly down-regulated in those from Dmp1-deficient mice. Selective Dmp1 deletion was found in 21% of the MMTV-D1 and D1T286A mammary carcinomas, and the Dmp1 heterozygous status significantly accelerated mouse mammary tumorigenesis with reduced apoptosis and increased metastasis. Overall, our study reveals a pivotal role of combined Dmp1 loss and cyclin D1 overexpression in breast cancer. As a key sensor and integrator of extracellular signals in early-to-mid G1 phase, cyclin D1 deregulation, including chromosomal translocation, gene amplification, or reduced degradation, results in tumorigenesis and has been linked to breast cancer and other human cancers.1Sutherland R.L. Musgrove E.A. Cyclins and breast cancer.J Mammary Gland Biol. 2004; 9: 95-104Crossref PubMed Scopus (183) Google Scholar, 2Arnold A. Papanikolaou A. Cyclin D1 in breast cancer pathogenesis.J Clin Oncol. 2005; 23: 4215-4224Crossref PubMed Scopus (319) Google Scholar Cyclin D1 drives cells to enter S phase by binding and activating the Cdk4/6 kinase. The cyclin D1/Cdk4 complex phosphorylates the retinoblastoma protein (pRb), which releases E2F transcriptional factors from pRb constraint. E2Fs then activate the transcription of genes required for cells to enter S phase.3Fu M.F. Wang C.G. Li Z.P. Sakamaki T. Pestell R.G. Minireview: cyclin D1: normal and abnormal functions.Endocrinol. 2004; 145: 5439-5447Crossref PubMed Scopus (809) Google Scholar Apart from its catalytic function, cyclin D1 also exerts a transcription regulation without the participation of Cdks, even though it is not a transcriptional factor. Cyclin D1 executes the transcriptional regulation through its interaction with transcriptional factors and chromatin modifiers.4Lamb J. Ramaswamy S. Ford H.L. Contreras B. Martinez R.V. Kittrell F.S. Zahnow C.A. Patterson N. Golub T.R. Ewen M.E. A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer.Cell. 2003; 114: 323-334Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, 5Musgrove E.A. Caldon C.E. Barraclough J. Stone A. Sutherland R.L. Cyclin D as a therapeutic target in cancer.Nat Rev Cancer. 2011; 11: 558-572Crossref PubMed Scopus (1000) Google Scholar For instance, it directly binds and activates estrogen receptor α (ERα) in breast cancer cell lines in a CDK-independent fashion.6Zwijsen R.M. Wientjens E. Klompmaker R. van der Sman J. Bernards R. Michalides R.J. CDK-independent activation of estrogen receptor by cyclin D1.Cell. 1997; 88: 405-415Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar By contrast, cyclin D1 interacts and inhibits the transcriptional activity of androgen receptor (AR), Myb-related protein B (B-Myb), E1A-binding protein p300, and NF-κB.7Knudsen K.E. Cavenee W.K. Arden K.C. D-type cyclins complex with the androgen receptor and inhibit its transcriptional transactivation ability.Cancer Res. 1999; 59: 2297-2301PubMed Google Scholar, 8Horstmann S. Ferrari S. Klempnauer K.H. Regulation of B-Myb activity by cyclin D1.Oncogene. 2000; 19: 298-306Crossref PubMed Scopus (55) Google Scholar, 9Fu M.F. Wang C.G. Rao M. Wu X.F. Bouras T. Zhang X.P. Li Z.P. Jiao X.M. Yang J.G. Li A.P. Perkins N.D. Thimmapaya B. Kung A.L. Munoz A. Giordano A. Lisanti M.P. Pestell R.G. Cyclin D1 represses p300 transactivation through a cyclin-dependent kinase-independent mechanism.J Biol Chem. 2005; 280: 29728-29742Crossref PubMed Scopus (78) Google Scholar, 10Rubio M.F. Fernandez P.N. Alvarado C.V. Panelo L.C. Grecco M.R. Colo G.P. Martínez-Noel G.A. Micenmacher S.M. Costas M.A. Cyclin D1 is a NF-κB corepressor.Biochim Biophys Acta. 2012; 1823: 1119-1131Crossref PubMed Scopus (16) Google Scholar Overall, these studies suggested that cyclin D1 regulates cell proliferation, growth, and differentiation, and its transcriptional regulatory activity has great potential significance in human cancer progression.5Musgrove E.A. Caldon C.E. Barraclough J. Stone A. Sutherland R.L. Cyclin D as a therapeutic target in cancer.Nat Rev Cancer. 2011; 11: 558-572Crossref PubMed Scopus (1000) Google Scholar, 11Bienvenu F. Jirawatnotai S. Elias J.E. Meyer C.A. Mizeracka K. Marson A. Frampton G.M. Cole M.F. Odom D.T. Odajima J. Geng Y. Zagozdzon A. Jecrois M. Young R.A. Liu X.S. 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K. of the in breast 2012; of Google Scholar The cyclin and mammary tumor development was significantly accelerated in with from to for cyclin and from to in D1T286A of D1 and mice mammary with those of the Dmp1 mammary of mice a Dmp1 in of the the of Dmp1 in cyclin tumor and D1 and mice mammary The mammary from Dmp1+/+;MMTV-cyclin D1 and Dmp1+/+;MMTV-D1T286A mice and as by in glands and a the from D1 and mice a as by increased and of mammary from Dmp1+/+;MMTV-cyclin D1 and Dmp1+/+;MMTV-D1T286A mice a significantly of apoptosis to those from D1 and mice as by of in in in and MMTV-D1 and of of to other including and in of D1 mice. of of to other including and in of mice with mammary The to other including and in of D1 The to other including and in of mice with mammary in a human breast with cyclin D1 also and a of mammary from D1 and mice with Dmp1 of cyclin D1 and mammary PubMed Scopus Google Scholar we to cyclin D1–induced mammary on the revealed of mammary of from D1 and mice that the loss of Dmp1 not the estrogen of cyclin D1–induced mammary Apart from mammary a of other tumor including and also found in both and found in the of Dmp1 in cancer A. T. P. M. G.A. K. of and in Full Text Full Text PDF PubMed Scopus Google Scholar, K. A. Dmp1 and tumor PubMed Scopus Google Scholar of mammary from D1 mice and of from mice to other including and 1 and cyclin D1 was detected in the but not in normal The expression of human D1 in both mammary and was by studies both and and that from the we detected of Dmp1 in the as in that the Dmp1 these results that Dmp1 to its the of cyclin and mammary It has been that Dmp1 is a of the Arf K. F. J.E. Dmp1 is for tumor and the of Arf and in PubMed Scopus Google Scholar, K. A. Dmp1 and tumor PubMed Scopus Google Scholar The Arf is by a of oncogenic to cells from to It has been that transcription factors in activating the through in to oncogenic N. M. Y. E. of and on expression PubMed Scopus Google Scholar Here, we that Dmp1 signals from cyclin D1 overexpression and binds to the on the Ink4a which is from the in the the Ink4a gene is by through The is from the transcription of the Ink4a Dmp1 directly binds to both mouse and human the was that in the Arf reduced binding of Dmp1 has been on other promoters as A. T. F. P. K. The transcription Dmp1 a transcriptional of and Cancer. 2010; Google Scholar that the of Dmp1 in gene regulation is dependent on the of the core is the K. M.F. of tumor suppressor gene expression and cell by transcription S A. 1999; PubMed Scopus Google Scholar, K. Regulation of the gene by a transcription by D-type Biol Chem. PubMed Scopus Google Scholar and core is has in Dmp1 binding the studies from our that Dmp1 regulates the by activating K. M.F. of tumor suppressor gene expression and cell by transcription S A. 1999; PubMed Scopus Google Scholar and with to its by F. T. R.L. E.A. K. Dmp1 physically interacts with and regulates and Res. 2012; PubMed Scopus Google Scholar Dmp1 has been as a cyclin transcription is known its role in cyclin and cyclin D1 not a it to with transcription factors to gene Dmp1 is the binding of Ink4a/Arf Arf and Ink4a promoters by cyclin which was by of pre-malignant mammary glands from cyclin D1 and D1T286A mice. the of increased and expression and induction of cell-cycle or cyclin D1 and its D1T286A that expression of cyclin D1 is to Arf and Ink4a in normal cells to oncogenic the activation of both Ink4a/Arf cyclin interaction was for to of binding of cyclin the cyclin D1 in with not activate these and cyclin D1 not to these promoters in Dmp1-deficient cells. we that Dmp1 in Arf and Ink4a gene activation in to cyclin D1 The that the D1 and D1T286A mice mammary is to loss of Dmp1 or overexpression of Ink4a/Arf as tumor studies to the of these in cyclin mammary found that cyclin D1 bound to and in breast cancer cells is in not is known to to cyclin J. Ramaswamy S. Ford H.L. Contreras B. Martinez R.V. Kittrell F.S. Zahnow C.A. Patterson N. Golub T.R. Ewen M.E. A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer.Cell. 2003; 114: 323-334Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar and our that cyclin D1 not activate the Arf with not we the that other transcriptional factors also in cyclin activation of the Arf studies that cyclin D1 interacts with transcription factors including and F. Jirawatnotai S. Elias J.E. Meyer C.A. Mizeracka K. Marson A. Frampton G.M. Cole M.F. Odom D.T. Odajima J. Geng Y. Zagozdzon A. Jecrois M. Young R.A. Liu X.S. Cepko C.L. Gygi S.P. Sicinski P. Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen.Nature. 2010; 463: 374-378Crossref PubMed Scopus (215) Google Scholar and we also in the Arf/Ink4a promoters not our the Arf/Ink4a studies to Dmp1 with or other transcription factors in Arf/Ink4a results the of induction not significantly and with a study that cell-cycle of M. A. The tumor suppressor inhibits through and Res. Google Scholar directly binds to and inhibits A. J. J. M. P. directly binds interaction with with the of Biol. 2005; PubMed Scopus Google Scholar The activity of also by K. M.F. of tumor suppressor gene expression and cell by transcription S A. 1999; PubMed Scopus Google Scholar it to study the of and its target genes in cyclin D1 cell-cycle arrest. that both cyclin and mammary was accelerated in mice. mammary from mice significantly increased in to those from mice because is of the target genes for of the human for of phase cell-cycle regulation J. Scholar that the activity of E2Fs by cyclin D1 is by study that the Dmp1 was in of mammary from D1 and in which Ink4a/Arf deletion was deletion of Dmp1 was also in P. F. T. K. of in human receptor and breast cancer Res. 2010; PubMed Scopus Google Scholar the role of in cyclin and mammary The study that the was significantly down-regulated in mammary but not in in to was significantly down-regulated in both and mammary in mammary from mice as as in the from Dmp1 A. T. P. M. G.A. K. of and in Full Text Full Text PDF PubMed Scopus Google Scholar, P. F. T. K. of in human receptor and breast cancer Res. 2010; PubMed Scopus Google Scholar The of expression in from that in accelerated tumor development in mice that in mice the was not K. F. J.E. Dmp1 is for tumor and the of Arf and in PubMed Scopus Google Scholar, A. T. P. M. G.A. K. of and in Full Text Full Text PDF PubMed Scopus Google Scholar the Ras and it is that overexpression of cyclin D1 loss of Ink4a and Arf accelerated tumorigenesis in K. M. The role of the cyclin in breast 2004; Full Text Full Text PDF PubMed Scopus Google Scholar The study is with a that mammary was not in cyclin Geng Y. Sicinski P. breast by cyclin D1 PubMed Scopus Google Scholar that cyclin D1 is a target of in mammary study that both Ink4a and Arf in to overexpression in mammary from P. F. T. K. of in human receptor and breast cancer Res. 2010; PubMed Scopus Google Scholar study also the reduced in pre-malignant mammary from D1 and D1T286A mice in both and to that in Dmp1 mice and The the of cyclin D1–induced mammary tumor in K. M. The role of the cyclin in breast 2004; Full Text Full Text PDF PubMed Scopus Google Scholar and the significantly accelerated in mice the also that other of Dmp1 in cyclin D1–induced mammary study also the significantly increased of cyclin D1–induced mammary in mice in to mice. cyclin D1 that to and we not that is found in human breast cancer our results role of Dmp1 in the mammary tumor induced by cyclin D1 and a potential mechanism of breast cancer metastasis. Currently, the of human breast cancer with cyclin D1 overexpression with or without and with of it to human breast cancer for the cyclin and to the of our for and for for MMTV-D1 J. for for human for J. for and for with binds and activates the The The of to the transcriptional is binding for is with a binding for on Ink4a or Arf with of with and of and with and of cells with increased of Dmp1 and the or its deletion or to in binding to The show the activation of the by with on human in cells. 1 and with of and with and of and 9: with and of and with and and and with and cells with the and increased of Dmp1 as with deletion of Dmp1 and expression of Arf/Ink4a in Dmp1+/+;MMTV-cyclin D1 and Dmp1+/+;MMTV-D1T286A mammary of the Dmp1 Dmp1 deletion in of Dmp1+/+;MMTV-cyclin D1 and Dmp1+/+;MMTV-D1T286A mammary B and of the Arf and Ink4a in Dmp1+/+;MMTV-cyclin D1 and Dmp1+/+;MMTV-D1T286A mammary by was as with of and D1 and mice. A D1 or mouse was with to D1 and mice. D1 and mice then with mice to mice with mice as with of cyclin D1 and Dmp1 in mammary glands from and D1 and mice. Mammary glands from to from of and for cyclin D1 and Dmp1 with of in mammary from and D1 and mice. of for in mammary from Dmp1+/+;MMTV-cyclin and mice. with with D1 binding in breast cancer cells. cyclin binding was 1 of cell of was with the cyclin D1 and to of cyclin D1 was with the Dmp1

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