Abstract

Physical associations between cyclins, viral oncogenes, and tumor suppressor genes imply a central role for cyclins in growth control. Cyclin D1 was identified as a candidate oncogene in tumor-specific DNA rearrangements. By virtue of DNA amplification, it contributes to 15% of breast cancers. Cyclin D1 protein is overexpressed in an additional 15-20% of breast cancers through unknown mechanisms. To evaluate its oncogenic potential, we overexpressed cyclin D1 in mammary cells in transgenic mice. Overexpression resulted in abnormal mammary proliferation and adenocarcinomas. We propose further studies of cyclin D1's role in breast cancer:
AIM 1 : Characterization of mechanisms regulating cyclin D1. Cyclin D1 protein is specifically increased in one-third of mammary carcinomas without accompanying increases in mRNA. We will evaluate mechanisms by which this increase in cyclin D1 protein might be regulated using tissue culture models, and we will identify factors regulating cyclin D1 during mammary growth and involution in vivo.
AIM 2 : Characterization of growth abnormalities in mammary epithelium overexpressing cyclin D1. The functions of cyclin D1 may be more complex than anticipated in vivo since our new preliminary data suggest that cyclin D1 may regulate apoptosis during mammary involution. We will further characterize this new phenotype. We will evaluate interactions between the genes involved in cyclin/cdk 4 complexes that might alter the role of cyclin D1 during mammary involution. By quantifying histologic changes, we will assess the overall function of cyclin D1 in mammary growth and involution.
AIM 3 : Assessment of second oncogenic events in adenocarcinomas in MMTV-cyclin D1 transcienic mice. Given the prolonged latency period of tumor development in cyclin D1 transgenic mice, the role of """"""""second hits"""""""" will be tested by random insertional mutagenesis using mouse mammary tumor virus infections and using differential display of mRNAs expressed at different levels during malignant transformation. Characterization of MMTV insertion sites by inverse PCR and identification of differentially expressed genes during cyclin D1-driven oncogenesis will be used to identify and clone oncogenes that may collaborate with cyclin D1 to cause breast cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA069069-04
Application #
6150208
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Cole, John S
Project Start
1997-04-01
Project End
2002-01-31
Budget Start
2000-02-11
Budget End
2001-01-31
Support Year
4
Fiscal Year
2000
Total Cost
$317,155
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Shearin, Abigail L; Hedan, Benoit; Cadieu, Edouard et al. (2012) The MTAP-CDKN2A locus confers susceptibility to a naturally occurring canine cancer. Cancer Epidemiol Biomarkers Prev 21:1019-27
Yang, Chuanwei; Hayashida, Tetsu; Forster, Nicole et al. (2011) 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. Cancer Res 71:937-45
Chen, Li; Shioda, Toshi; Coser, Kathryn R et al. (2010) Genome-wide analysis of YY2 versus YY1 target genes. Nucleic Acids Res 38:4011-26
Yang, Chuanwei; Chen, Li; Li, Cuiqi et al. (2010) Cyclin D1 enhances the response to estrogen and progesterone by regulating progesterone receptor expression. Mol Cell Biol 30:3111-25
Schmidt, Emmett V; Ravitz, Michael J; Chen, Li et al. (2009) Growth controls connect: interactions between c-myc and the tuberous sclerosis complex-mTOR pathway. Cell Cycle 8:1344-51
Ravitz, Michael J; Chen, Li; Lynch, Mary et al. (2007) c-myc Repression of TSC2 contributes to control of translation initiation and Myc-induced transformation. Cancer Res 67:11209-17
Trent, Sally; Yang, Chuanwei; Li, Cuiqi et al. (2007) Heat shock protein B8, a cyclin-dependent kinase-independent cyclin D1 target gene, contributes to its effects on radiation sensitivity. Cancer Res 67:10774-81
Yang, Chuanwei; Trent, Sally; Ionescu-Tiba, Viviana et al. (2006) Identification of cyclin D1- and estrogen-regulated genes contributing to breast carcinogenesis and progression. Cancer Res 66:11649-58
Yang, Chuanwei; Ionescu-Tiba, Viviana; Burns, Karen et al. (2004) The role of the cyclin D1-dependent kinases in ErbB2-mediated breast cancer. Am J Pathol 164:1031-8
Nahta, Rita; Trent, Sally; Yang, Chuanwei et al. (2003) Epidermal growth factor receptor expression is a candidate target of the synergistic combination of trastuzumab and flavopiridol in breast cancer. Cancer Res 63:3626-31

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