Date of Award

5-2024

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Biosciences

First Advisor

Shailja Pathania

Second Advisor

Kourosh Zarringhalam

Third Advisor

Jill A. Macoska, Changmeng Cai

Abstract

Women carrying BRCA1 (B1) mutations face an elevated risk of developing breast cancer, yet effective preventive strategies remain limited. To design innovative prevention methods, it is critical to understand the early events driving tumorigenesis. Here we present a unique mouse model which is conditionally heterozygous for B1 and deleted for Trp53, specifically in the mammary epithelial cells, and forms triple-negative mammary tumors under replication stress. Our single-cell RNA sequencing analysis, spanning various stages of mammary tumorigenesis in this model, reveals early tumor-promoting transcriptomic alterations. We identify a distinct, proliferative bi-potent cell population expressing both luminal progenitor and basal epithelial markers, uniquely enriched in Brca1 heterozygous mammary tissue upon replication stress. Notably, the transcriptomic changes in this population correlate with poor outcomes in human breast cancer. Transcriptomic analysis, combined with transcription factor analysis, along the trajectory from normal to precancerous and tumor stages, implicates the AP-1 complex, specifically the FRA-1 transcription factor, as an early driver in BRCA1 mutant breast cancer. Furthermore, pseudo-time analysis along this trajectory identifies alveolar luminal progenitor cells as the likely cell-of-origin. Luminal cells also show reduced efficiency of DNA damage repair when compared to basal cells. In conclusion, we have established a Brca1 heterozygous mouse model for studying the effects of DNA replication stress on breast cancer and have identified early precancerous transcriptomic changes stemming from BRCA1 haploinsufficiency and replication stress. This study provides critical insights into the molecular mechanisms that drive breast cancer in BRCA1 mutation carriers.

Comments

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