Breast cancer remains the second highest cause of cancer-related deaths among women despite significant improvements in diagnosis and treatments. Women with aggressive triple-negative breast cancer (TNBC) face poor patient outcomes and lack effective targeted therapies. Despite extensive efforts to characterize this subtype, the oncogenic drivers of TNBC remain elusive and pose a challenge that must be overcome. Widespread chromosomal instability is a characteristic feature of TNBC, making it difficult to decipher between genes that drive cancer development from those that play a bystander role. Little is known about what gives rise to the extensive genomic instability of TNBC, and presents a major deficit in our scientific and clinical knowledge. To maintain genomic integrity, cells utilize a DNA damage response (DDR) mechanism that functions to sense damaged DNA, repair it efficiently and commit cells to death if the damage is irreparable. Activation of this system is critically important in suppressing the onset of malignancy. Occurrences of altered DDR have been observed in pre-malignant lesions as well as in malignant cells, but not in normal/healthy tissue, indicating that perturbations in this system may contribute to tumorigenesis and its associated genomic aberrations. Knowing how TNBC tumors are able to bypass or disrupt the DDR system will be critical to understanding their patterns of genomic instability, their phenotypic properties, and their therapeutic sensitivities. Thus, the gol of this proposal is to identify the drivers of genomic instability in TNBC, and to use these insighs to guide the development of personalized therapies for patients with this disease. In order to accurately distinguish driver genes from bystander genes we propose to create novel models of TNBC by inducing specific genetic alterations in mammary epithelial cells either in cell culture or in a mouse model. These genetically controlled model systems will enable us to determine causality of specific DDR mutations in breast cancer development and importantly, the genomic instability phenotype typical for TNBC. The insights gleaned from the proposed work may provide the means to determine the most effective treatment regimens, and to prevent over-treatment of patients where certain chemotherapies may not be effective. Support of this project will also advance the short- and long-term goals of an emerging young, female, minority scientist, Dr. Katerina Fagan-Solis. The tailored mentoring and training plan ensures research support, access to core facilities and equipment to enhance technical capabilities, and multiple opportunities to attend both scientific and career-focused workshops, seminars, national meetings, and frequent involvement with other prominent scientists to develop networking, presentation, and communication skills. Awarding this fellowship will be vital to the growth and success of Dr. Fagan-Solis as an independent researcher and scientist.

Public Health Relevance

Defects in the DNA damage repair system (DDR), specifically in proteins that regulate homologous recombination, result in increased genomic instability and have recently been implicated as being drivers of tumorigenesis in both familial and sporadic breast cancers. The objective of this proposal is to elucidate the origins of genomic instability through the study of Rad17 and other DDR proteins in the causative events leading to the complex pattern of chromosomal rearrangements that is typical for triple-negative breast cancer (TNBC). This proposal may provide new insights into the therapeutic vulnerabilities of genomically unstable TNBC tumors (as well as other malignancies that are characterize by extensive chromosomal instability), and help to establish a means to define personalized therapeutic regimens for patients with TNBC, with the hope that this strategy may ultimately lead to an improvement in survival rates for this aggressive disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F09A-D (20)L)
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Mcguirl, Michele
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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