# Effects of Brca1 Heterozygosity on Mammary Gland Biology

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2020 · $33,208

## Abstract

Project Summary/Abstract
Effects of Brca1 Heterozygosity on Mammary Gland Biology
Germline heterozygous BRCA1 mutations hugely predispose women to breast and ovarian cancer; however,
the basis for the tissue specificity of this effect remains obscure. Burgeoning evidence suggests that this
gene’s mutation may cause phenotypic changes in mammary tissue prior to tumor formation. Uncovering the
precise nature and mechanisms of the changes in the precancerous breast will prove vital to developing
improved preventative treatments for this familial cancer syndrome. Unfortunately, clinical progress in this field
is stymied by disagreements in the scientific literature concerning which mammary populations are perturbed;
indeed, this issue is a subcase of the broader ambiguity surrounding the cellular composition of the normal
mammary gland.
 In this proposal, we describe plans to use mass cytometry to systematically test our hypothesis that
Brca1 heterozygosity induces the aberrant accumulation of one or more mammary cell types and that these
populations display altered differentiation and DNA repair phenotypes which ultimately make them more
tumorigenic than other mammary cells. In Aim 1, I will analyze mammary cell populations using single-cell
proteomics via mass cytometry, which will enable a high-resolution understanding of the cell types present
throughout normal mammary gland development and will allow a more precise understanding of the nature of
alterations in the development and premalignant phenotype of Brca1+/- mammary glands. In Aim 2, I will
functionally characterize the differentiation potential, hormone responsiveness, and DNA repair to assess
whether Brca1+/- mammary cells possess differentiation blocks and deficient DNA repair and whether such
alterations are restricted to mammary populations altered in frequency in Aim 1. Finally, in Aim 3, I will take
advantage of a novel mouse model developed in the Brugge lab of Brca1-associated breast carcinogenesis to
test whether distinct mammary epithelial populations have differing tumorigenic capacity. In sum, the
experiments proposed herein will greatly advance our knowledge of how the normal mammary gland is
organized and how it is altered in the context of Brca1 heterozygosity. In addition, I will be directly addressing
the tumorigenic potential of various mammary populations, thus providing direct evidence of the cell-of-origin in
this familial cancer syndrome.

## Key facts

- **NIH application ID:** 9924249
- **Project number:** 5F31CA228200-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Gary Kenneth Gray
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,208
- **Award type:** 5
- **Project period:** 2018-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924249

## Citation

> US National Institutes of Health, RePORTER application 9924249, Effects of Brca1 Heterozygosity on Mammary Gland Biology (5F31CA228200-03). Retrieved via AI Analytics 2026-06-07 from https://api.ai-analytics.org/grant/nih/9924249. Licensed CC0.

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