It is still unclear how BRCA1 suppresses rumorigenesis in normal mammary epithelial cells and why BRCA1 mutation carriers develop basal-like breast carcinomas. In vivo, BRCA1 exists as a heterodimer with the BARD1 protein, and many of its biological properties are mediated through the BRCA1/BARD1 complex. We recently used conditional mutagenesis to show that basal-like breast carcinomas can be induced in mice by mammary-specific inactivation of either Bardl or Brcal. The common basal-like phenotype shared by the Bardl- and Brcal-mutant mammary carcinomas implies that BRC A1-mediated tumor suppression is implemented by the BRCA1/BARD1 heterodimer. Meanwhile, biochemical studies have show that the heterodimer is a potent ubiquitin E3 ligase. Moreover, we have found that BRCA1/BARD1 induces the formation of K6-linked polyubiquitin chains that are structurally distinct from the conventional K48-linked chains that mark cellular proteins for proteasomal degradation, and recent studies indicate that proteins bearing K6-linked chains are not targeted for turnover. Furthermore, since the E3 activity of BRC A1/BARD 1 is ablated by tumor-associated BRCA1 missense mutations, the enzymatic function of the heterodimer is likely to be essential for tumor suppression. Thus, to elucidate the molecular mechanisms of BRCA1- mediated tumor suppression, we will evaluate how the BRCA1/BARD1 heterodimer and its associated E3 ligase activity promote tumor suppression and investigate why disruption of BRCA1/BARD1 function leads to formation of basal-like breast cancer. In particular, we will 1) determine whether the E3 ligase activity of BRCA1/BARD1 is required for normal development and BRCA1-mediated tumor suppression, 2) examine the role of this E3 ligase activity in double-strand DNA break repair and cell cycle checkpoint control, 3) explore the molecular mechanisms of ubiquitin-mediated signaling by BRCA1 /BARD 1, and 4) examine interactions between the BRCA1 and PTEN pathways in the development of basal-like breast cancer.

Public Health Relevance

Germline mutations of the BRCA1 gene are a major cause of familial breast cancer, and women bearing these lesions face a extraordinary lifetime risk (>80%) of developing breast cancer. Moreover, most of the tumors that are arise in BRCA1 mutation carriers display the basal-like phenotype, and thus fall within the clinical subgroup of breast cancer associated with the poorest prognosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA097403-09
Application #
8380090
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$336,585
Indirect Cost
$131,180
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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