The risk of developing breast cancer increases as women get older. The maintenance of DNA represents a fundamental and continuous challenge to every cell in the body. Genomic instability is a hallmark of most cancers as well as a hallmark in aging. Recent evidence strengthened the link between the maintenance of genome integrity, cancer susceptibility and aging. These conditions can be caused by germline mutations in BRCA1, which is an essential caretaker protein in the surveillance of DNA damage. Impaired oxidative stress response plays an important role in breast oncogenesis. Beta-catenin was shown to be a co-factor for the FOXO family, which promotes survival by inducing cell cycle arrest and quiescence in response to oxidative stress. We observed that wild-type (WT) BRCA1, but not mutated BRCA1, interacts with beta-catenin and increases beta-catenin protein expression by promoting lysine-6-linked ubiquitination. Oxidative stress reagent H2O2 increased colocalization and the interaction of BRCA1 with beta-catenin in the nucleus. WT-BRCA1, but not mutated BRCA1, protected the nuclear active form of beta-catenin during oxidative stress responses. The expression of this form of beta-catenin was lower or absent in most of BRCA1 familial breast cancer tissues. Therefore, we hypothesize that: 1) BRCA1 acts as a sensor in regulating beta-catenin mediated oxidative stress and FOXO function;and 2) low expression of WT-BRCA1 or mutations in BRCA1 leads to impaired response to oxidative stress and causes genomic instability, resulting in increased risk of breast cancer in women. Therefore, we aim to examine the effects of BRCA1 on beta-catenin protein expression and stability and to analyze the role of BRCA1 in beta-catenin mediated oxidative stress response. Thus, we specifically propose the following aims:
Aim 1 : To investigate the role of Brca1 in the expression and distribution of beta-catenin and its targets (cyclin D1 and c-Myc) during mammary gland development in Brca1 mutant mice, in which Brca1 exon 11 is specifically deleted from the mammary glands by using the Cre-loxP system.
Aim 2 : To characterize the role of BRCA1 as a sensor in regulating the beta-catenin and FOXO interaction during oxidative stress signaling. Results from this work will enhance our knowledge of the molecular events that drive sporadic breast and ovarian cancer development and progression in aging women.
By defining the targets that are altered in mutated BRCA1-linked breast and ovarian cancers and providing insights into the BRCA1 pathways, this study may lead to potential new therapeutic strategies for the prevention, early diagnosis and treatment of familial breast and ovarian cancers. In addition, results from this work will enhance our understanding of the molecular events that drive breast and ovarian cancers in aging women, and may link BRCA1 and beta-catenin to oxidative stress and breast oncogenesis.
