# Deciphering the mechanism underlying BRCA1 breast cancer development

> **NIH NIH R35** · DANA-FARBER CANCER INST · 2020 · $1,053,423

## Abstract

Project Summary/Abstract
Inherited BRCA1 mutations very often result in high frequency breast and ovarian cancer in affected families.
This proposal is aimed at illuminating key steps that occur after menarche in tumor-free, BRCA1-mutated
mammary epithelium and contribute in a major way to future BRCA1 breast cancer (BrCa) development.
Our published data and work in progress suggest the existence of a series of interrelated biochemical steps
that, when interrupted, result in the conversion of ostensibly normal, BRCA1- mutated breast epithelial cells
into an abnormal, dedifferentiated, unusually primitive, and likely pre-malignant state. This change involves the
loss of function of any member of a group of 6 particular genes which translates into a breakdown in DNA
damage control which, in turn, promotes a breakdown in mammary epithelial differentiation. In breast cells
these genes normally communicate with one another, functionally, as if they were components of a biologically
important pathway dedicated, in part, to BrCa suppression. Indeed, their protein products form a distinct
molecular complex which also contains the BRCA1 tumor suppressor protein, p220, and this complex operates
in ways that suggest a major role for it in such a pathway.
Among the 6 other complex members (BRG1, FancD2, CtIP,NUMB, HES-1, and BARD1), some (e.g. FancD2,
BRG1) are somatically mutated in sporadic BrCa. Another (Numb) is a known BrCa suppressor in animals and
a supporter of normal stem cell proliferation, and at least 5 of the 6 must be present and bind to p220 for the
entire complex to form and mammary epithelial differentiation to proceed normally. Our work in progress also
suggests that the integrity of this complex is required to prevent BRCA1 BrCa from developing.
The proposed research will test the validity of this hypothesis along with the physiological importance of such a
pathway, using a combination of cutting edge methods. Included will be an effort to a) test for lineage
relationships between failed mammary epithelial cell (MEC) DNA damage repair and MEC dedifferentiation and
between MEC dedifferentiation and BRCA1 tumor development and b) to decipher the mechanisms governing
the interrelationships of these events.
A major component of these efforts will be the application of single cell RNAseq to assess the above-noted
lineage relationships and mammary epithelium- focused genomic CRISPR and protein overexpression screens
to detect individual proteins that participate in these important steps in BRCA1 BrCa development. We will use
a newly developed mouse model in these experiments.!

## Key facts

- **NIH application ID:** 9990763
- **Project number:** 5R35CA242143-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** DAVID Morse LIVINGSTON
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,053,423
- **Award type:** 5
- **Project period:** 2019-08-07 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990763

## Citation

> US National Institutes of Health, RePORTER application 9990763, Deciphering the mechanism underlying BRCA1 breast cancer development (5R35CA242143-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9990763. Licensed CC0.

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