Elucidation of the Molecular Mechanisms for Aberrant Expression of Breast Cancer Specific Gene 1 in Invasive and Metastatic Breast Carcinomas
Annual rept. 1 Jun 2003-31 May 2004
VETERANS AFFAIRS PALO ALTO HEALTH CARE SYSTEM CA
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The abnormal expression of Breast Cancer Specific Gene 1 BCSG1 in malignant mammary epithelial cells is strongly linked to the development and progression of breast cancer. Our previous studies have identified DNA demethylation as an important mechanism for breast cancer cells to express BCSG1. We have demonstrated that similar to other protooncogenes such as c-myc, BCSG1 gene becomes selectively hypomethylated, which allows its abnormal expression in breast tumor cells. in turn, tumor cells expressing BCSG1 gain growth advantage. However, little is known about how BCSG1 exerts its oncogenic functions in breast cancer cells. in order to uncover the mechanisms whereby BCSG1 induces disease progression and malignant conversion, we have searched for BCSG1-interacting proteins through a yeast two-hybrid screening and co-immunoprecipitation assays. These studies led to the identification of BubR1, a critical mitotic checkpoint kinase, being the cellular target of BCSG1. We have also obtained new evidence from several lines of investigations to demonstrate that BCSG1 expression in breast cancer cells directly inhibits the mitotic checkpoint function and induces aneuploidy in a BubR1-dependent manner. These new findings suggest that induction of aneuploidy by BCSG1 is likely an important contributing factor to the development of advance-staged breast carcinoma.
- Anatomy and Physiology
- Medicine and Medical Research