# A premalignant chronology of cell-state variability in basal-like breast cancer

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $622,712

## Abstract

PROJECT SUMMARY/ABSTRACT
Basal-like carcinoma is a rapidly-progressing and highly variable subtype of breast cancer that arises
spontaneously (often in African Americans) or in genetically predisposed women. Such tumors are believed to
arise from the functional loss of the BRCA1 and TP53 tumor suppressors in uncommitted basoluminal
progenitors of the breast. However, it has been challenging to dissect the origins of the disease for lack of
appropriate tools, making it difficult to conceive of how the cell-state variability of premalignant mutants gives
rise to basal-like breast cancer. The long-term goal of this work is to identify the critical cellular and molecular
transitions underlying basal-like breast cancer genetics. The current application deploys a novel genetically
engineered mouse model called mosaic analysis of double markers (MADM), which randomly deletes murine
Brca1–Trp53 in transit-amplifying progenitors of the mammary gland. In MADM, stochastic deletion is
genetically defined by coexpression of GFP, allowing locally expanded premalignant lesions to be visualized
within the gland before the onset of basal-like disease. We found that premalignant expansion is accompanied
by extensive recruitment of specific immune subsets, suggesting they play crucial roles in tumorigenesis. Our
objective is to combine MADM with innovative methods for dissociation-free transcriptomics that will identify
cell-state variabilities within mutant epithelial cells and the infiltrating immune lineages of a premalignancy.
The hypothesis is that epithelial-cell plasticity and the stromal microenvironment coordinately diversify mutant
lesions, revealing premalignant transcriptional states that ultimately progress to basal-like cancer in the breast
and mammary gland. The aims of the proposal are: 1) To define shared premalignant trajectories of
basoluminal diversification triggered by BRCA1–TP53 deficiency in mice and humans. 2) To deconvolve the
immune heterogeneities that are locally paired with specific premalignant ecosystems for basal-like breast
cancer. 3) To functionally validate cell states important for progression by using genetic, pharmacologic, and
paracrine perturbations that homogenize intrinsic or extrinsic variability of premalignant cells ex vivo. Co-PIs
Janes and Zong are thought leaders in their respective fields of intratumor cell-state heterogeneity and
genetically engineered mouse modeling with a multi-year track record of collaboration. Together with a pair of
senior clinicians, the team is poised to have a significant overall impact on our understanding of basal-like
breast tumorigenesis.

## Key facts

- **NIH application ID:** 10768617
- **Project number:** 5R01CA256199-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Kevin A Janes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $622,712
- **Award type:** 5
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768617

## Citation

> US National Institutes of Health, RePORTER application 10768617, A premalignant chronology of cell-state variability in basal-like breast cancer (5R01CA256199-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10768617. Licensed CC0.

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