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Access Type

WSU Access

Date of Award

January 2017

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Michele L. Cote

Abstract

Despite converging incidence rates for breast cancers by race, disparities in mortality persist where black women suffer from poorer prognosis compared to white counterparts. To understand the clinical, demographic, and molecular characteristics underlying these disparities, we examined differences among patients with breast cancer to understand the role of human epidermal growth factor receptor 2 (HER2) status, age, and race/ethnicity among women diagnosed with hormone receptor-positive breast cancer, and disparities in surgical therapy among female patients with early stage young-onset breast cancer. Benign breast disease, another known risk factor for breast cancer, includes a histological spectrum of lesions, could contribute to disparities in survival among both black and white women is benign breast disease as little is known about benign breast tissue from black women. To better characterize the risk of breast cancer among black women with benign breast disease, we profiled the clinicopathology and molecular characteristics of benign breast lesions among black women who subsequently developed breast cancer. Using the metropolitan Detroit benign breast disease cohort, we identified black women with benign breast lesions subsequently diagnosed with breast cancer. Gene expression profiling of benign breast disease tissue and Cox proportional hazards modeling were used to evaluate transcriptional variations associated with time to breast cancer. 1,802 genes were significantly associated with a shorter time to breast cancer diagnosis. The greatest transcriptional variation associated with time to diagnosis was histone lysine demethylase 4C (KDM4C), a histone-modifying enzyme. Given that information regarding the genomic and transcriptomic alterations of KDM4C and the KDM4 subfamily in different subtypes of breast cancer remains largely incomplete, we conducted a meta-analysis of KDM4A-D in breast cancer and identified associations among recurrent copy number alterations, gene expression, and breast cancer subtypes. We demonstrated that KDM4C amplification and overexpression was observed in aggressive, basal-like breast cancer tissues. Inflammatory disease ranked as the top disorder, and nearly a fifth of the genes classified in the estrogen biosynthesis pathway were significantly associated with time to breast cancer. Taken together, our findings identify molecular precursors for time to cancer among black women with benign breast disease. These results identify increased expression of critical molecular determinants, including KDM4C, and pathways that are significantly associated with shorter time to subsequent breast cancer development among black women. Further studies to better characterize the molecular profiles of benign breast and breast cancer lesions can lead to development of molecular classifiers for breast cancer risk and diagnosis among black women with benign breast lesions.

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