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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (O1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Whitehead Institute for Biomedical Research
United States
Zip Code
Bailey, Shannon T; Westerling, Thomas; Brown, Myles (2015) Loss of estrogen-regulated microRNA expression increases HER2 signaling and is prognostic of poor outcome in luminal breast cancer. Cancer Res 75:436-45
Hines, William C; Su, Ying; Kuhn, Irene et al. (2014) Sorting out the FACS: a devil in the details. Cell Rep 6:779-81
Yamamoto, Shoji; Wu, Zhenhua; Russnes, Hege G et al. (2014) JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell 25:762-77
Jeselsohn, Rinath; Yelensky, Roman; Buchwalter, Gilles et al. (2014) Emergence of constitutively active estrogen receptor-? mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res 20:1757-67
Lu, Haihui; Clauser, Karl R; Tam, Wai Leong et al. (2014) A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol 16:1105-17
Pathania, Shailja; Bade, Sangeeta; Le Guillou, Morwenna et al. (2014) BRCA1 haploinsufficiency for replication stress suppression in primary cells. Nat Commun 5:5496
Hu, Yiduo; Petit, Sarah A; Ficarro, Scott B et al. (2014) PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair. Cancer Discov 4:1430-47
McAllister, Sandra S; Weinberg, Robert A (2014) The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol 16:717-27
Hill, Sarah J; Rolland, Thomas; Adelmant, Guillaume et al. (2014) Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage. Genes Dev 28:1957-75
Hill, Sarah J; Clark, Allison P; Silver, Daniel P et al. (2014) BRCA1 pathway function in basal-like breast cancer cells. Mol Cell Biol 34:3828-42

Showing the most recent 10 out of 89 publications