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

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2022 · $34,928

## Abstract

In the funded parent grant 1R01 CA256199-01A1 entitled “premalignant chronology of cell-state variability in
basal-like breast cancer”, we proposed to comprehensively and progressively analyze gene expression profiles
of mutant cells during the premalignant stage of basal-like breast cancer to understand how cell state plasticity
could lead to tumor progression. 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 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. The aims of the parent R01 are to use transcriptomic
analysis: 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. The project proposed by the supplement
candidate is distinct from but perfectly complements with the experiments proposed in the parent R01: while
the parent R01 focuses on delineating cell state plasticity based on gene expression profiles, her project
approaches the problem from phenotype-guided functional interventions. In Specific Aim 1, she plans to
investigate the involvement of aberrant hormonal signaling during premalignant progression and test potential
treatment strategies. In Specific Aim 2, she will investigate whether premalignant hyperproliferation can be
exploited using PARPi treatment. As a whole, these complementary experiments should not only allow us to
dive more deeply into key mechanisms of premalignant progression of bas...

## Key facts

- **NIH application ID:** 10598886
- **Project number:** 3R01CA256199-01A1S1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Kevin A Janes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $34,928
- **Award type:** 3
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598886

## Citation

> US National Institutes of Health, RePORTER application 10598886, A premalignant chronology of cell-state variability in basal-like breast cancer (3R01CA256199-01A1S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10598886. Licensed CC0.

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