Master of Science
Singh, Krishna K.
Despite mounting concern over the increased risk of cardiovascular disease in breast cancer patients, studies evaluating the common genetic/molecular link between these diseases are limited. Mutations in the breast cancer susceptibility genes (BRCA1&2) predispose carriers to breast and ovarian cancers due to compromised DNA damage repair capacity leading to DNA damage accumulation; in cancer cells, and in other cell-types including endothelial cells, causing atherosclerotic hallmarks of endothelial dysfunction/apoptosis. We present a new understanding of BRCA2’s protective functionality in the setting of atherosclerosis. Studies have thus far demonstrated that while loss of endothelial BRCA2 in mice does not affect a molecular or functional baseline phenotype, endothelial cell-specific loss of BRCA2 exacerbates high-fat diet-induced atherosclerosis in ApoE-/- mice. This study illuminates BRCA2 as a potential therapeutic target in cardiovascular disease and suggests a requirement for studies evaluating the genetic predisposition of BRCA2-mutation carriers for increased risk of atherosclerosis and other cardiovascular diseases.
Summary for Lay Audience
In Canada, as in most developed countries, the cardiovascular disease atherosclerosis which is the buildup of vessel-occluding plaque, is a leading cause of illness and death. According to the most recent data, one in five deaths in Canada is due to atherosclerosis-associated cardiovascular dysfunction. Despite great medical advances, therapies are urgently needed to improve cardiovascular function in atherosclerosis. Endothelial cells, which line the innermost layer of blood vessels, play important roles in maintaining blood vessel function. Understanding the mechanisms underlying abnormal endothelial function may serve to uncover novel therapeutic approaches to treat atherosclerosis and associated cardiovascular dysfunctions. DNA is the genetic material present in every cell type, and it is prone to damage by various stressors. BRCA2 is a protein molecule, which maintains DNA integrity by repairing the damaged DNA. Loss of BRCA2 function causes breast and ovarian cancer. DNA damage not only causes cancer but also plays important role in the development of cardiovascular diseases. Our aim is to understand if the loss of endothelial BRCA2 results in increased endothelial cell death, endothelial dysfunction, and if it also promotes atherosclerosis-associated cardiovascular diseases. In this thesis, we will use an animal model of atherosclerosis which lacks BRCA2, only in their endothelial cells. We aim to investigate if there will be increased atherosclerosis-associated endothelial dysfunction and endothelial cell death after feeding these animals a high fat diet. Our study will delineate a new role of BRCA2 in atherosclerosis, which may help identify BRCA2 as a new therapeutic target to treat cardiovascular diseases. Our study may also indicate a cancer-independent increased susceptibility of cardiovascular disease development in carriers of a BRCA2 mutation.
Michels, David C.R., "Endothelial Cell-specific Loss of Breast Cancer Susceptibility Gene 2 Exacerbates Atherosclerosis" (2021). Electronic Thesis and Dissertation Repository. 8243.
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