# Crosstalk between BRCA1 and Transcription in Breast Cancer

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2022 · $421,744

## Abstract

ABSTRACT
 Most BRCA1-asociated breast tumors are basal-like, yet they originate from luminal progenitor cells.
BRCA1 plays important roles in double strand break (DSB) repair and response to DNA replication stress.
However, it remains a conundrum as to whether these ubiquitously important functions of BRCA1 are sufficient
to account for its cell lineage-specific breast tumor suppression. Filling this longstanding intellectual disconnect
could inform more effective risk assessment and disease prevention. Our mouse genetics work identified
unexpected functional antagonism between BRCA1 and COBRA1, a dedicated transcription elongation factor
important for luminal gene transcription. This BRCA1/COBRA1 crosstalk regulates luminal progenitor function,
luminal transcription-related DSB precursors, and mammary tumorigenesis in a DSB repair-independent
manner. In a parallel investigation using clinical samples, we found that cancer-free BRCA1 mutation carriers
accumulate DSB precursors specifically in their breast luminal epithelial cells. Based on this groundwork, we
hypothesize that, through its crosstalk with COBRA1-dependent transcription elongation machinery,
BRCA1 prevents preferential accumulation of DSB precursors at luminal genes and thus reduces
genome instability in luminal cell compartment. We will use mouse genetics and clinical samples to
elucidate the impact of BRCA1/COBRA1 antagonism on luminal homeostasis, DSB precursor production, and
breast tumorigenesis. The concept to be validated in our proposed work clearly departs from the prevailing
DNA repair-centric paradigm. Furthermore, the DNA repair-independent BRCA1/COBRA1 antagonism points
to a previously unappreciated direction for elucidating BRCA1 tumor suppressor function and preventing
BRCA1-associated breast cancer. When successfully executed, our studies promises to lay a solid conceptual
foundation to reconcile an enduring disconnect concerning BRCA1-associated breast cancer, thus catapulting
understanding of BRCA1 cancer biology to a new level.

## Key facts

- **NIH application ID:** 10438697
- **Project number:** 5R01CA220578-06
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Rong Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $421,744
- **Award type:** 5
- **Project period:** 2017-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438697

## Citation

> US National Institutes of Health, RePORTER application 10438697, Crosstalk between BRCA1 and Transcription in Breast Cancer (5R01CA220578-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10438697. Licensed CC0.

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