Student Theses, Dissertations and Capstones

Document Type

Dissertation - NSU Access Only

Degree Name

Doctor of Philosophy (PhD) in Pharmacy

First Advisor

Jean Latimer

Defense Date

1-1-2022

Abstract

Breast cancer is the most common cancer affecting women in the United States. Breast cancer recurrence is a significant issue associated with a much higher risk of death. The goal of treatment is for it to be sufficiently customized for each breast cancer subtype as to minimize treatment morbidity and mortality. Identifying early-stage breast cancer patients at high-risk of recurrence is crucial to avoiding unnecessary treatment. Prognostic biomarkers have been developed to estimate the risk of breast cancer recurrence at early stages, based on multiple cancer-related gene panels, such as MammaPrint and Oncotype DX. However, these tests are not suitable for breast tumors that are estrogen receptor negative and have more than three positive lymph nodes. One of our goals was to establish biomarkers that can include patients outside these exclusion criteria. We hypothesized that nucleotide excision repair (NER) genes would provide some of these prognostic biomarkers based on our previous work. We now show an association between recurrence and NER deficiency using the functional unscheduled DNA synthesis assay in 33 primary tumor explants. Using three non-recurrent and three recurrent explants derived from these primary cultures, we were able to validate the functional assay findings using gene expression analysis. We created addition model systems for study by isolating and subcloning invasive and non-invasive cells from each subgroup to identify prognostic biomarkers for disease aggressiveness and progression. Further validation of the role of NER and other pathways of repair as biomarkers of aggressiveness was achieved using unsupervised pathway analyses. These analyses have shown meaningful associations between DNA repair deficiency, invasiveness, and recurrence. All major DNA repair pathways were significantly downregulated in all invasive cells relative to non- invasive cells. The pathway analysis validated the correlation between downregulation of NER gene expression (and additional pathways of repair) with in vivo (clinical) aggressiveness (recurrence) or in vitro aggressiveness (invasiveness). This study has also uncovered additional oncogenes and tumor suppressor genes that repeatedly appear in key pathways identified by unsupervised analysis. These genes, in combination with NER genes, constitute a new paradigm for prognostic testing of early-stage breast cancer.

Subject Categories

Pharmacy and Pharmaceutical Sciences

Keywords

Breast Cancer; Invasiveness; NER; Nucleotide Excision Repair; Recurrence

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