DF/HCC Program Affiliation

Cancer Genetics
Breast Cancer

Research Abstract

One focus of our laboratory is to elucidate the pathways through which the oncogene cyclin D1 contributes to breast cancer. Cyclin D1 is overexpressed in greater than 50% of breast cancers. Two modes of action have been proposed to underlie the oncogenic actions of cyclin D1. In one, cyclin D1 acts in concert with its catalytic partners to influence proliferation. In the other, cyclin D1 affects the activity of transcription factors, doing so without the involvement of cdks.

To functionally dissect the mechanism of cyclin D1 action in human cancer we employed gene expression profiling. Our analyses of the expression patterns of thousands of genes across hundreds of human tumor specimens suggest that overexpressed cyclin D1 engages a cdk-independent transcriptional program in human cancer. Further, our analyses suggest the involvement of a transcription factor, C/EBP beta, in the regulation of genes affected by cyclin D1 in human cancer.

C/EBP beta is a significant participant in the differentiation of the mammary epithelium and its aberrant expression contributes to the neoplastic process. Motivated by these and our own findings, we are exploring the possibility that overexpression of cyclin D1 aberrantly alters the differentiation program of mammary epithelial cells in a C/EBP beta-dependent manner and that its ability to do so is central to its oncogenic actions in the mammary gland.

Another area of investigation centers on the product of the retinoblastoma tumor susceptibility gene (Rb). Murine embryos nullizygous for Rb die mid-gestation with a number of defects. Our previous cell culture-based experiments have suggested that the retinoblastoma protein (pRb) and the product of the proto-oncogene ras operate in a common pathway to control cellular differentiation. We have extended these observations to the mouse, showing that deletion of either of two ras isoforms, K-ras or N-ras, rescues a unique subset of the developmental defects associated with nullizygosity of Rb, resulting in a significant extension of lifespan. We are currently delineating the pathways through which Rb and ras genetically interact to affect embryonic development.

Mice that are heterozygous for Rb (one allele of Rb) are tumor prone. In consonance with our embryological studies, we have found that loss of ras modifies the tumor phenotype of Rb heterozygotes by affecting differentiation. Further, we have discovered that loss of a particular ras isoform can promote the development of metastatic tumors. Current efforts are aimed at understanding how the genetic interaction between Rb and ras effects metastasis and to extend our genetic analysis in mice to human cancer.

Publications

• Takahashi C, Ewen ME.Genetic Interaction between Rb and N-ras: Differentiation Control and Metastasis.Cancer Res 2006 Oct 1;66(19):9345-9348.
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• Takahashi C, Contreras B, Bronson RT, Loda M, Ewen ME.Genetic interaction between Rb and K-ras in the control of differentiation and tumor suppression.Mol Cell Biol 2004 Dec;24(23):10406-15.
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• Ewen ME, Lamb J.The activities of cyclin D1 that drive tumorigenesis.Trends Mol Med 2004 Apr;10(4):158-62.
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• Lamb J, Ewen ME.Cyclin D1 and molecular chaperones: implications for tumorigenesis.Cell Cycle 2003 Nov-Dec;2(6):525-7.
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• Lamb J, Ramaswamy S, Ford HL, Contreras B, Martinez RV, Kittrell FS, Zahnow CA, Patterson N, Golub TR, Ewen ME.A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer.Cell 2003 Aug 8;114(3):323-34.
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• Takahashi C, Bronson RT, Socolovsky M, Contreras B, Lee KY, Jacks T, Noda M, Kucherlapati R, Ewen ME.Rb and N-ras function together to control differentiation in the mouse.Mol Cell Biol 2003 Aug;23(15):5256-68.
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• Lee KY, Ladha MH, McMahon C, Ewen ME.The retinoblastoma protein is linked to the activation of Ras.Mol Cell Biol 1999 Nov;19(11):7724-32.
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• Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, Pestell RG, Hinds PW, Dowdy SF, Brown M, Ewen ME.Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4.Mol Cell Biol 1997 Sep;17(9):5338-47.
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