LIKE BREAST CANCERS Hann-Hsiang Chao A dissertation submitted to

EXAMINATION OF THE BRCA1-DEPENDENT DNA REPAIR PATHWAY IN BASALLIKE BREAST CANCERS

Hann-Hsiang Chao

A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum in Genetics and Molecular Biology

Chapel Hill 2012

Approved By: Charles Perou, PhD William Kaufmann, PhD W. Kimryn Rathmell, MD, PhD Kristy Richards, MD, PhD Melissa Troester, PhD

UMI Number: 3512604

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UMI 3512604 Copyright 2012 by ProQuest LLC. All rights reserved. This edition of the work is protected against unauthorized copying under Title 17, United States Code.

ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, MI 48106 - 1346

UMI Number: 3512604

All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent on the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion.

UMI 3512604 Copyright 2012 by ProQuest LLC. All rights reserved. This edition of the work is protected against unauthorized copying under Title 17, United States Code.

ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, MI 48106 - 1346

©2012 Hann-Hsiang Chao ALL RIGHTS RESERVED ii

ABSTRACT HANN-HSIANG CHAO: Examination of the BRCA1-Dependent DNA Repair Pathway in Basal-like Breast Cancer (Under the direction of Dr. Charles Perou) Human breast cancer is a diverse disease, exhibiting variety in morphology, natural history, and therapeutic response. Multiple studies have shown that breast tumors can be segregated into distinct subtypes, characterized by similarities in the genes they express. One subtype, called basal-like breast tumors (BBT), represents 10-20% of breast cancer diagnoses and is typically associated with poor outcomes. Our work has shown that BBT occurs with significantly higher frequency in women with germline mutations in breast cancer 1 (BRCA1). Given the link between BRCA1-germline mutations and BBT, we proposed to determine whether the BRCA1-dependent DNA repair pathway is deficient during sporadic BBT formation. Our initial step was to identify BBT specific regions of aberration and determine if they affected important genetic pathways. One region located on chromosome 5q contained multiple BRCA1-dependent repair pathway genes. These genes exhibited frequent co-associated loss with each other and with other cancer relevant genes. Exogenous disruption of these genes in normal breast epithelial cell lines increased sensitivity to DNA damage and impaired BRCA1 localization and function. We further characterized the genomic instability aspect of BBT by examining a previously undetectable form of genomic aberration we termed microiii

aberrations. These small-scale genomic changes (