In Vivo Analysis of the BRCA1 Breast Cancer Development Pathway

$426,385P01FY2018CANIH

Whitehead Institute For Biomedical Res, Cambridge MA

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Abstract

This proposal is based on results from our laboratory showing that primary skin fibroblasts and primary normal- appearing mammary epithelial cells {MECs) from healthy BRCA1 {B1)+/- women are defective in the repair of stalled replication forks (stalled replication fork repair=SFR). Thus, they are haploinsufficient for this function. The same cells do not appear to be defective in homologous recombination-based double strand break repair, a canonical BRCA1 biochemical function. These cells will be tested for multiple, other B1 functions with the goal of determining whether they perform the other, established B1 functions normally. Preliminary indications are that they are intact for at least 1 other B1 function- centrosome proliferation control. Defective repair of stalled replication forks is a common human cancer- promoting force. The experiments to be performed here are aimed at learning whether a B1-SFR defect and any other haploinsufficient B1 functions present in ostensibly normal B1+/-mammary epithelium represent early drivers of B1 breast cancer development. Positive results would open new avenues to the development of disease mechanism-based B1 breast cancer prevention and therapeutic strategies.

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