Modeling Estrogen-Induced Genomic Alteration in BRCA1-Mutant Mammary Cells Using iPSCs
Abstract
Women who carry an inherited BRCA1 mutation (BRCA1mut) have an increased risk of breast cancer. BRCA1mut carriers have a 55%-65% chance of developing breast cancer by age 70, while women in the general population only have an 8% chance. Although BRCA1 protein functionality is well studied, it remains unclear as to why BRCA1mut particularly increases the risk of breast cancer. Clinical studies have shown strong linkages between estrogen and the incidence of breast cancer in BRCA1mut carriers. With use of oral contraceptive pills, younger age at first childbirth, early menarche, and late menopause being the primary risk factors for BRCA1mut carriers. Interestingly, women with BRCA1mut more often develop triple-negative breast cancer, which is estrogen-receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative, and is more commonly associated with basal-like breast cancer (BLBC). This subtype of breast cancer does not rely on estrogen. How does estrogen exposure lead to BLBC in BRCA1mut carriers? Clinical studies have found that the breast tissue in BRCA1mut carriers has more breast stem or precursor cells, which can mature into fully functional breast cells, and thus result in less milk secretion during lactation. Basic research also demonstrated that normal BRCA1 is an important regulator for proper breast development. This study will address the overarching challenge in “identifying determinants of breast cancer initiation, risk, or susceptibility” by elucidating the mechanisms of BRCA1mut-associated breast cancer initiation. Researchers found that estrogen can be metabolized to genotoxic chemicals in mammary epithelial cells through ER-independent biological processes. These metabolites can induce DNA damage, DNA breaks, gene mutations, and ultimately breast cancer. The enzymes catalyzing estrogen to genotoxic chemicals are highly expressed in breast tissue. As BRCA1 protein suppresses tumor development by repairing DNA damage and maintaining genomic integrity, BRCA1mut-caused protein function deficiency may render breast cell sensitive to the genotoxicity induced from estrogen-derived chemicals. Taken together, we hypothesize that BRCA1mut-harboring cells may continuously accumulate genetic mutations via periodic estrogen level changes in development, which may contribute to breast cancer initiation. Research studies using either mouse models or established cell models to investigate the underlying mechanisms of BRCA1mut-induced breast cancer have limitations for studying BRCA1mut-related breast cancers. First, established cancer cell models after long-term culture cannot adequately represent normal breast cells from the same patients. Second, common cell culture methods do not represent the extensive complexity of human tissue. We propose to utilize our recently established, induced pluripotent stem cell (iPSC)-based system to recapitulate human mammary gland development. iPSCs are multipotent stem cells converted via mature adult cells from patients. iPSCs, like embryonic stem cells, can be induced to differentiate to almost all types of cells. We have established iPSC lines from patients carrying BRCA1mut and women with normal BRCA1. Further, we have successfully induced iPSCs to form three-dimensional (3D) mammary microtissues. Currently there is no BRCA1mut mammary epithelial cell model. In this proposal, we will use these iPSC lines to study how breast development-associated hormones, specifically estrogen, affect genomic changes in derived normal breast cells and tissue, both in vitro and in vivo. Our findings will help uncover genetic mechanisms and hallmarks for BRCA1mut-specific effects on breast cancer development, which may be used in predicting breast cancer risk in BRCA1mut carriers. In the long term, this project could lead to the identification of molecular targets for chemoprevention in mutation carriers and thus
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810067
Entities
People
- Xaiojiang Cui
Organizations
- Cedars-Sinai Medical Center
- United States Army