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    Awarded Grants
    DNA Repair and the Etiology of Estrogen Receptor Positive Breast Cancer

    Scientific Abstract:
    In the United States, more than 210,000 cases of breast cancer are diagnosed each year leading to over 40,000 deaths. One of the prototypic molecular targets for breast cancer therapy has been estrogen receptor alpha (ER), a member of the nuclear hormone receptor superfamily. Ligand bound ER has a major role in inducing cellular proliferation in normal breast epithelium. Epidemiological studies have linked higher lifetime estrogen exposure to increased risk of developing breast cancer. Most human breast cancers express ER in the majority of the malignant epithelial cell population, which is striking given that ER protein is detected in only 5% of normal breast epithelial cells. Therefore, two important unresolved questions are why predominantly ER+ tumors make up the majority of human breast cancer cases and what genetic factors predispose these cells to tumorigenic expansion. Answers to these questions may reveal new ways to inhibit the pathogenesis of ER+ breast cancer. Using a new animal model, we have been able to permanently label normal ER+ mammary epithelial cells by constitutive expression of beta-galactosidase prior to malignant conversion. Beta-galactosidase expression in these cells correlated with ER localization using immunofluorescence. The ER+ cell population in this model undergoes expansion during the early stages of tumorigenesis. Expression profiling of these and ER+ human breast epithelial cells revealed decreased expression of double strand break repair genes. Reduced expression of these repair proteins may sensitize ER+ breast epithelial cells to environmental DNA damage. We hypothesized that ER+ breast cancer arises by expansion of the DNA repair deficient ER+ breast epithelial cell population. These cells possess clinically relevant phenotypes including increased susceptibility to carcinogens and antiproliferative therapies. We will test these hypotheses by characterizing double strand break repair and transformation in these and ER- control cells, genetically alter these processes, and apply these results to mammary cancer pathogenesis in vivo using a novel transgenic model. Understanding how deficient DNA repair allows selective expansion of tumorigenic ER+ epithelial cells will create new therapeutic opportunities for preventing this most common form of breast cancer.

    Lay Abstract:
    In the United States, more than 210,000 cases of breast cancer are diagnosed each year leading to over 40,000 deaths. An important target for breast cancer therapy is estrogen receptor (ER). ER has a major role in making normal breast cells divide. Higher lifetime estrogen exposure results in increased risk of developing breast cancer. Most human breast cancers express ER in the majority of cancer cells, which is striking because ER is detected in only 5% of normal breast cells. Therefore, two important unanswered questions are why predominantly ER+ tumors make up most of human breast cancer and what genetic factors program these cells to become cancer. Answers to these questions may reveal new ways to prevent or treat ER+ breast cancer. Using a new model, we have been able to permanently label normal ER+ mammary cells before they become cancer cells. The ER+ cell population in this model undergoes expansion during the early stages of cancer. These and ER+ human breast cells produce decreased amounts of proteins involved in repair of DNA. Reduced expression of these repair proteins may sensitize ER+ breast cells to environmental DNA damage. We hypothesized that ER+ breast cancer arises by expansion of the DNA repair deficient ER+ breast epithelial cell population. These cells possess important clinical characteristics including increased susceptibility to carcinogens and chemotherapy drugs. We will test these hypotheses by characterizing DNA repair and carcinogenesis in these cells, genetically alter these processes, and apply these results to breast cancer using a new model. Understanding how deficient DNA repair allows expansion of potentially cancerous ER+ cells will create new opportunities for preventing this most common form of breast cancer.