DF/HCC Program Affiliation

Gynecologic Cancer

Research Abstract

In collaboration with Dr. Lawrence Zukerberg (MGH Department of Pathology), we have identified a protein that is lost with high frequency in endometrial and ovarian carcinoma. The protein, known as Cables, is a negative regulator of the cell cycle via its ability to enhance the inhibitory phosphorylation of the Cdk2 protein (a key modulator of the G1-S phase transition in mitosis). Consequently, loss of function would theoretically result in uncontrolled cellular proliferation as a first step towards cancer. We have completed studies showing that this cell cycle regulatory protein is regulated by hormones in human endometrial epithelial cells. We observe a consistent loss of this protein in almost all endometrial cancer biopsies and, most importantly, intermittent loss of the protein in those biopsies with pre-cancerous atypical hyperplasia. In addition, we have generated a gene mutant mouse, which is deficient in this cell cycle regulatory protein. Cables mutant mice have evidence of endometrial hyperplasia at an early age and develop endometrial cancer following exposure to chronic estrogen. This finding served as the impetus to evaluate Cables expression in human ovarian cancer. Similar to that which is observed in human endometrial cancer samples, there is a significant loss of nuclear Cables expression associated with human ovarian serous and endometrioid cancer. The functional significance of Cables as a tumor suppressor in the ovary is currently being explored.

Publications

• Lee HJ, Sakamoto H, Luo H, Skaznik-Wikiel ME, Friel AM, Niikura T, Tilly JC, Niikura Y, Klein R, Styer AK, Zukerberg LR, Tilly JL, Rueda BR.Loss of CABLES1, a cyclin-dependent kinase-interacting protein that inhibits cell cycle progression, results in ger
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• Gonzalez RR, Cherfils S, Escobar M, Yoo JH, Carino C, Styer AK, Sullivan BT, Sakamoto H, Olawaiye A, Serikawa T, Lynch MP, Rueda BR.Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (
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