FUNCTIONS OF CYCLIN D1 IN BREAST CANCER

Summary

Principal Investigator: Emmett Schmidt
Abstract: DESCRIPTION (provided by applicant): Cyclin D1 contributes to 15-40% of breast cancers through DNA amplification and overexpression. It is associated with estrogen receptor positive tumors, and predicts both a poor prognosis for ER+ tumors and resistance to anti-estrogen treatments. MMTV-cyclin D1 mice develop ER positive adenocarcinomas whose development is not blocked by inhibition of cyclin dependent kinase 4/6 using an MMTV-p16 transgene. Cyclin D1 is also downstream of multiple mitogenic pathways including erbB2, and its function is required for erbB2 transformation. We propose additional studies of the role of cyclin D1 in breast cancer as both a direct cause of ER positive tumors and as a mediator of erbB2's oncogenic function. Aim 1 will evaluate Cdk 4-independent activities of cvclin D1, including interactions between cyclin D1 and the estrogen receptor, that contribute to breast cancer. MMTV-cyclin D1 will be crossed with MMTV-AIB1 transgenic mice to genetically test the role of cyclin D1/ER interactions. Mutant cyclin D1s incapable of Cdk 4 interactions (mu/KE) and lacking steroid coactivator interactions (mu/LALA) will be expressed in model breast cell lines and using MMTV in transgenic mice to evaluate the role of those activities in D1 oncogenesis. We will determine whether cyclin D1 regulates specific estradiol-regulated genes or directly alters ER coactivator/corepressor promoter binding in breast cancer cells. Aim 2 will evaluate the proposed erbB2 ? cvclin D1 pathway in breast cancer. Expression patterns of erbB2 and cell cycle regulators will be evaluated in invasive breast cancers to confirm our preliminary observation that erbB2 is expressed non-redundantly with p16 and pRb loss. Cell cycle functions of erbB2 will be tested in transgenic models to determine whether cyclin D1 can rescue erbB2-deficiency phenotypes and establish whether erbB2 expression is sufficient to deregulate cell cycle progression without need for additional loss of p16 or gain of cyclin D1. Aim 3 will use microarray analysis of laser capture microdissected hyperplasia and tumors from cyclin D1 and erbB2 transgene-induced tumors to identify genes involved in neoplastic progression from hvperlasia to cancer. Our initial screen has identified six genes whose altered regulation is seen in both human and mouse invasive adenocarcinoma. They are predominately genes involved in cell death regulation and we show several are estradiol regulated. These candidate genes involved in neoplastic progression will be validated by analysis of human cancers, in functional assays, and by assessment of their regulatory controls.
Funding Period: 1997-04-01 - 2009-06-30
more information: NIH RePORT

Top Publications

  1. pmc Mammary tumorigenesis following transgenic expression of a dominant negative CHK2 mutant
    Eunice L Kwak
    Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA
    Cancer Res 66:1923-8. 2006
  2. pmc The MTAP-CDKN2A locus confers susceptibility to a naturally occurring canine cancer
    Abigail L Shearin
    Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
    Cancer Epidemiol Biomarkers Prev 21:1019-27. 2012
  3. pmc Growth controls connect: interactions between c-myc and the tuberous sclerosis complex-mTOR pathway
    Emmett V Schmidt
    Cancer Research Center at Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA
    Cell Cycle 8:1344-51. 2009
  4. pmc Genome-wide analysis of YY2 versus YY1 target genes
    Li Chen
    Cancer Research Center at Massachusetts General Hospital, Boston, MA 02114, USA
    Nucleic Acids Res 38:4011-26. 2010
  5. pmc Cyclin D1 enhances the response to estrogen and progesterone by regulating progesterone receptor expression
    Chuanwei Yang
    Cancer Research Center at Massachusetts General Hospital, 55 Fruit Street, GRJ 9th floor, Boston, MA 02114, USA
    Mol Cell Biol 30:3111-25. 2010
  6. pmc The integrin alpha(v)beta(3-5) ligand MFG-E8 is a p63/p73 target gene in triple-negative breast cancers but exhibits suppressive functions in ER(+) and erbB2(+) breast cancers
    Chuanwei Yang
    Cancer Research Center at Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Cancer Res 71:937-45. 2011
  7. ncbi Identification of cyclin D1- and estrogen-regulated genes contributing to breast carcinogenesis and progression
    Chuanwei Yang
    Massachusetts General Hospital Cancer Research Center, Massachusetts General Hospital Cancer Center Harvard University, 55 Fruit Street, GRJ 904, Boston, MA 02114, USA
    Cancer Res 66:11649-58. 2006
  8. ncbi Heat shock protein B8, a cyclin-dependent kinase-independent cyclin D1 target gene, contributes to its effects on radiation sensitivity
    Sally Trent
    Oxford Cancer Centre, Department of Radiotherapy, Churchill Hospital, Oxford, United Kingdom
    Cancer Res 67:10774-81. 2007
  9. pmc c-myc Repression of TSC2 contributes to control of translation initiation and Myc-induced transformation
    Michael J Ravitz
    Cancer Research Center at Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    Cancer Res 67:11209-17. 2007

Scientific Experts

  • Emmett Schmidt
  • Chuanwei Yang
  • Li Chen
  • Cuiqi Li
  • Mary Lynch
  • Sally Trent
  • Abigail L Shearin
  • Mary C Lynch
  • Dennis Sgroi
  • Toshi Shioda
  • Michael J Ravitz
  • Eunice L Kwak
  • Francis Galibert
  • Benoit Hedan
  • Suzanne A Erich
  • Matthew Breen
  • Daniel L Faden
  • Heidi G Parker
  • Elaine A Ostrander
  • Jérôme Abadie
  • Patrick Devauchelle
  • Edouard Cadieu
  • Catherine Andre
  • Andrea Grone
  • Danielle M Karyadi
  • Maud Rimbault
  • Erika M Kwon
  • John Cullen
  • Gerard R Rutteman
  • Tetsu Hayashida
  • Dejun Shen
  • Leif W Ellisen
  • Nicole Forster
  • Karen S Anderson
  • Shyamala Maheswaran
  • Cathrin Brisken
  • Kathryn R Coser
  • Viviana Ionescu-Tiba
  • Sang Kim
  • Lan Lan
  • Robert D Cardiff
  • Jianmin Zhang
  • Daniel A Haber

Detail Information

Publications9

  1. pmc Mammary tumorigenesis following transgenic expression of a dominant negative CHK2 mutant
    Eunice L Kwak
    Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA
    Cancer Res 66:1923-8. 2006
    ..The increased rate of tumor formation in MMTV-CHK2-D347A mice, compared with the relatively low incidence in chk2-null mice, provides a model to study modifiers of CHK2-dependent transformation...
  2. pmc The MTAP-CDKN2A locus confers susceptibility to a naturally occurring canine cancer
    Abigail L Shearin
    Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
    Cancer Epidemiol Biomarkers Prev 21:1019-27. 2012
    ..Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15% to 25% of Bernese Mountain Dogs (BMD)...
  3. pmc Growth controls connect: interactions between c-myc and the tuberous sclerosis complex-mTOR pathway
    Emmett V Schmidt
    Cancer Research Center at Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA
    Cell Cycle 8:1344-51. 2009
    ..Further experiments will be needed to clarify the mechanisms underlying this important connection, and evaluate its overall contribution to cancers caused by TSC loss or Myc gain...
  4. pmc Genome-wide analysis of YY2 versus YY1 target genes
    Li Chen
    Cancer Research Center at Massachusetts General Hospital, Boston, MA 02114, USA
    Nucleic Acids Res 38:4011-26. 2010
    ..Our studies show that human YY2 is not redundant to YY1, and YY2 is a significant regulator of genes previously identified as uniquely responding to YY1...
  5. pmc Cyclin D1 enhances the response to estrogen and progesterone by regulating progesterone receptor expression
    Chuanwei Yang
    Cancer Research Center at Massachusetts General Hospital, 55 Fruit Street, GRJ 9th floor, Boston, MA 02114, USA
    Mol Cell Biol 30:3111-25. 2010
    ..Additionally, its regulation of the progesterone receptor identifies a novel role for cyclin D1 in ovarian hormone control of breast development and breast carcinogenesis...
  6. pmc The integrin alpha(v)beta(3-5) ligand MFG-E8 is a p63/p73 target gene in triple-negative breast cancers but exhibits suppressive functions in ER(+) and erbB2(+) breast cancers
    Chuanwei Yang
    Cancer Research Center at Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Cancer Res 71:937-45. 2011
    ..Its potential use as a serum biomarker that contributes to the pathogenesis of triple-negative breast cancers urges continued evaluation of its differential functions...
  7. ncbi Identification of cyclin D1- and estrogen-regulated genes contributing to breast carcinogenesis and progression
    Chuanwei Yang
    Massachusetts General Hospital Cancer Research Center, Massachusetts General Hospital Cancer Center Harvard University, 55 Fruit Street, GRJ 904, Boston, MA 02114, USA
    Cancer Res 66:11649-58. 2006
    ....
  8. ncbi Heat shock protein B8, a cyclin-dependent kinase-independent cyclin D1 target gene, contributes to its effects on radiation sensitivity
    Sally Trent
    Oxford Cancer Centre, Department of Radiotherapy, Churchill Hospital, Oxford, United Kingdom
    Cancer Res 67:10774-81. 2007
    ..Taken together, our results show that some of cyclin D1's effects on radiation sensitivity are CDK and p21 independent and identify HSPB8 as a candidate CDK-independent cyclin D1 target that can mediate its effects...
  9. pmc c-myc Repression of TSC2 contributes to control of translation initiation and Myc-induced transformation
    Michael J Ravitz
    Cancer Research Center at Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    Cancer Res 67:11209-17. 2007
    ..Together, these findings show that regulation of TSC2 can contribute to the effects of Myc on cell proliferation and neoplastic growth...