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.

Public Health Relevance

BRCA1 is a gene that normally suppresses breast cancer development. Women with inherited BRCA1 mutations develop breast cancer at markedly elevated rates. The details of how the disease develops are a mystery. The work proposed here is aimed at understanding the specific molecular steps by which BRCA1 breast cancer develops in otherwise normal breast tissue. Success will create major new opportunities to develop more effective means of prevention and treatment than currently exist.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA080111-16
Application #
8633706
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (O1))
Project Start
2014-02-01
Project End
2019-01-31
Budget Start
2014-05-02
Budget End
2015-01-31
Support Year
16
Fiscal Year
2014
Total Cost
$436,738
Indirect Cost
$68,537
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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