Gestational Exposure to Soy Isoflavones and Epigenetic Regulation of Breast Cancer Risk
Abstract
Rationale, Objectives, and Aims: The BRCA-1 gene encodes a tumor suppressor protein involved in DNA repair and transcription control. In women who carry one copy of the mutated BRCA-1 gene, the silencing of the second wild-type copy is associated with a high probability (~60%-80%) of developing hereditary breast cancers. In contrast, sporadic breast cancers, which represent the vast majority (~90%) of breast tumor cases, do not have mutations in the BRCA-1 gene but have absent or markedly reduced levels of BRCA-1 protein. Therefore, the objective of this proposal is to explore the mechanisms that contribute to silencing of BRCA-1 production. Identifying these mechanisms has important implications for the prevention of both hereditary and sporadic breast tumors. Aims: This proposal deals with mechanisms that go under the definition of epigenetics, i.e., changes in gene expression that do not involve modifications of the DNA sequence and that contribute to the etiology of breast cancer. Because epigenetic changes are reversible, they represent a viable target in breast cancer prevention and treatment. For example, sporadic breast cancers that have an epigenetic modification at the BRCA-1 gene called CpG methylation (C-cytosine, G-guanine) have apparent characteristics of hereditary BRCA-1 mutation tumors in spite of the fact they carry normal (non-mutated) BRCA-1 sequence. Therefore, aims of the application are to examine how interactions between genetic and epigenetic events impact the production of BRCA-1 and the development of mammary tumors. Overarching Challenge Addressed by This Research, Type of Patients, and Clinical Implications: The CpG methylation of the BRCA-1 gene is associated with reduced BRCA-1 expression in 50%-60% of higher histological grade sporadic tumors. Sporadic tumors that lack BRCA-1 are usually triple-negative (TNBC) with reduced or absent expression of three important targets for endocrine therapies: the estrogen receptor-alpha (ERalpha), progesterone receptor (PR), and epidermal growth factor receptor-2 (Her2) (ER-/PR-/Her2-). Although TNBCs account for only 20% of breast cancer cases, their poor prognosis and lack of treatment options are responsible for a disproportionate number of breast cancer deaths. Therefore, our overarching challenge is to identify the mechanisms that link epigenetic repression of BRCA-1 to the development of TNBCs. These discoveries may lead to the development of new clinical therapies for patients with TNBCs. Projected Time to Achieve a Patient-Related Outcome: Information from animal models and population studies suggest that mammary tumor promotion in adult life is influenced by prior exposure to carcinogens in utero. We hypothesize that in utero exposure to dietary compounds that prevent BRCA-1 silencing antagonize the development of TNBCs in the offspring. The rationale for this hypothesis stems from preliminary work that uncovered a positive association between in utero CpG methylation at the BRCA-1 gene and reduced BRCA-1 expression in mammary tissue of offspring. These findings suggest that the risk of breast cancer may be related to maternal exposure and epigenetic changes that occurred in the fetus during gestation. Also, our preliminary data indicate that mammary tumors that share some characteristics of TNBC have BRCA-1 that is CpG methylated. Therefore, we anticipate we would be able to achieve patient-related outcomes in 3 years. These outcomes may include new knowledge of the mechanisms that contribute to TNBCs and the development of new prognostic markers. Likely Impact of This Study on Ending Breast Cancer: Genistein is a common food isoflavone with antagonistic properties toward enzymes that place methylation marks at CpGs. This proposal integrates genetic, epigenetic, and dietary factors with broad impact for breast cancer eradication. Data generated by this project may lead to the development of prognostic signatures and t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510387
Entities
People
- Donato Romagnolo
Organizations
- United States Army
- University of Arizona