Somatic Mutation Rate as Determinant of Breast Cancer Penetrance in BRCA1/2 Familial Cases

Project Details

Description

Our proposed research will address one overarching challenge of the breast cancer landscape: how to link mechanistically BRCA1/2 mutations to breast cancer risk. The results of the project will fill a critical black box in our understanding of how these mutations modulate breast cancer risk. The steady decline in breast cancer mortality over the course of the past ~10 years has been attributed to both improvements in breast cancer treatment and early detection. Routine early mammographic screening is recommended for women over the age of 40. Several screening tools are also now available to screen young women with family history of breast and/or ovarian cancer. Most notoriously, mutations in the BRCA1/2 genes are associated with ~80% increased risk of breast cancer development. Yet, the molecular mechanism that transform non-tumor cells into invasive breast carcinoma cells in these patients remains obscure. This represents a significant gap of knowledge, especially given that these are the two most well characterized cancer susceptibility genes. Remarkable and extensive work from many investigators has followed the initial discovery in 1994 of the first for BReast CAncer gene (BRCA1). As result, we now know that the BRCA1 gene product is a tumor suppressor gene that assists in the repair of damaged DNA. Germline mutations in both BRCA1 and BRCA2 significantly increase the risk for breast and ovarian cancer; genetic testing for women with family history is now routine. Yet, the mechanism responsible for the initial transformation process and how modifiers affect risk remain unknown. This is mainly because most of the molecular work thus far has been performed on tumor tissue from carriers or using models (in culture and mice). While much is still to be gained from these studies, the focus on genomic changes of tumor cells limits the identification of the modulator of risk. Our goal in this application is to shift the focus on premalignant cells when clinical intervention is known to have the most impact. The major impediment to study non-tumor cells has been the technical limitations associated with these studies. We present here an innovative approach to overcome this barrier. We recently developed a test for measuring mutations in normal cells. To achieve this is much more difficult than measuring the germline mutations that predispose individuals to disease, for example, the aforementioned BRCA1 or BRCA2 mutations. Such mutations are present in each and every cell and can be detected in the blood or any other tissue. Mutations in body cells and tissues, however, occur randomly and differ from cell to cell. They can only be identified by decoding the DNA of single cells. This is exactly the procedure that we developed and published in Nature Methods, the top journal in its field. It is this method that we now wish to apply to study mutations in normal breast cells of BRCA1 or BRCA2 carriers. Furthermore, we also propose to study the molecular mechanism of how hormonal exposure (contraceptives, pregnancy, hormone replacement therapy) acts as a modifier of penetrance by affecting the somatic mutation rate in these cells and therefore modulating risk. Hormonal exposure, especially estrogen, is a well-known risk factor for breast cancer as well as other tumor types. Thus far, most of the work has focused on the effect that hormones have on cell proliferation and how hormonal exposure hijacks this mechanism to fuel the proliferation of cancer cells. For over a decade, estrogen has been included in the list of compounds recognized as cancer-causing agents by the National Institute of Environmental Health Sciences (NIEHS). Here we propose the novel hypothesis that estrogen acts as a modifier of risk in BRCA1/BRCA2 carriers because of its ability to directly induce DNA mutations. Because mammary epithelial cells of women with BRCA1/BRCA2 mutations have weakened their ability to repair DNA damage,

StatusActive
Effective start/end date5/1/19 → …

Funding

  • U.S. Army: $908,334.00

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