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

Award Number: R01CA256199
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $589,939 )
2026	2026	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	5	12/11/2025	NON-COMPETING CONTINUATION	$589,939
														Subtotal = $589,939

Issue Date FY: 2025 ( Subtotal = $695,399 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	003	4	8/29/2025	SUPPLEMENT FOR EXPANSION	$3,991
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	4	12/23/2024	SUPPLEMENT FOR EXPANSION	$35,922
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	002	4	6/3/2025	NON-COMPETING CONTINUATION	$65,547
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	4	12/19/2024	NON-COMPETING CONTINUATION	$589,939
														Subtotal = $695,399

Issue Date FY: 2024 ( Subtotal = $691,624 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	3	12/29/2023	NON-COMPETING CONTINUATION	$589,939
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	003	3	4/17/2024	SUPPLEMENT FOR EXPANSION	$3,627
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	002	3	4/16/2024	NON-COMPETING CONTINUATION	$32,773
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	3	1/3/2024	SUPPLEMENT FOR EXPANSION	$65,285
														Subtotal = $691,624

Issue Date FY: 2023 ( Subtotal = $713,464 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	2	1/25/2023	NON-COMPETING CONTINUATION	$642,376
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	2	2/7/2023	SUPPLEMENT FOR EXPANSION	$71,088
														Subtotal = $713,464

Issue Date FY: 2022 ( Subtotal = $690,414 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	1	12/14/2021	NEW	$655,486
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	1	9/9/2022	SUPPLEMENT FOR EXPANSION	$34,928
														Subtotal = $690,414

Grand Total All Awards = $3,380,840

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

Award Number: R01CA256199

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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