Identification of genetic interactors of BRCA2 in ES cell-based model

Thursday, October 11, 2012 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center, Building 45	NCI	GEN/GENOM-7

* FARE Award Winner

Authors

• X. Ding
• S. Philip
• S.K. Sharan

Abstract

Mutations in breast cancer susceptible genes, BRCA1 and BRCA2 are the genetic factors conferring highest risk to develop breast cancer. Although BRCA proteins are known to maintain genomic stability mainly by homologous recombination-mediated DNA damage repair, detailed mechanisms of how BRCA loss induces tumorigenesis remain unclear. Interestingly, while inactivation of both alleles of BRCA1 or BRCA2 genes is necessary for tumor development, their loss in normal cells affects cell viability, indicating that cells lacking BRCA1 or 2 are able to survive and predisposed to tumorigenesis due to mutations in other genes such as those involved in cell cycle regulation or DNA damage response. In the current study, we identified some of the candidate genes using a mouse embryonic stem (mES) cell-based insertional mutagenesis screening. Abnormally high expression of these genes rescued Brca2 loss-induced lethality in mES cells. One candidate encodes a PDZ domain-containing protein, GIPC3. The GIPC3-rescued cells were hypersensitive to DNA damaging agents and exhibited an overall increase in genomic instability. We are examining if Gipc3 overxpression can rescue the lethality of Brca2ko/ko embryos and contribute to tumorigenesis in Brca2ko/+ mice. We are also examining the expression of GIPC3 in human BRCA2-deficient tumors.

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