Mark E. Ewen, PhD

Mark E. Ewen, PhD

Researcher

Contact Information

Office Phone Number

(617) 632-2206

Fax

(617) 632-5417

Biography

Mark E. Ewen, PhD

Dr. Ewen received his PhD from the University of Chicago in 1988. His postdoctoral work, performed at DFCI, involved the study of tumor suppressors and cell-cycle regulation. In 1992, he joined DFCI, where his laboratory focuses on elucidating molecular mechanisms associated with the development of cancer.

Researcher

Physician

Associate Professor of Medicine, Harvard Medical School

Research

    Mechanisms of Cell Proliferation, Differentiation, Transformation, and Metastasis

    One focus of our laboratory is elucidating the pathways through which the oncogene cyclin D1 contributes to breast cancer. Two modes of action have been proposed to explain the oncogenic actions of cyclin D1, which is overexpressed in greater than 50% of breast cancers: cyclin D1 acts in concert with its catalytic partners to influence proliferation; and cyclin D1 affects the activity of transcription factors, without the involvement of cdks. We used gene expression profiling to functionally dissect the mechanism of cyclin D1 action in human cancer. 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. Our analyses also 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. Based on these 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 (Rb) tumor susceptibility gene. Murine embryos nullizygous for Rb die mid-gestation with a number of defects. Our previous cell-culture-based experiments 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. Consistent 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 affects metastasis and to extend our genetic analysis in mice to human cancer.

    Locations

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    Dana-Farber Cancer Institute

    450 Brookline Avenue Dana 730 Boston, MA 02215
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    Dana-Farber Cancer Institute

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    Dana-Farber Cancer Institute

    450 Brookline Avenue Dana 730 Boston, MA 02215
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    42.3374, -71.1082

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