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Functional Significance of individual p53 mutations in determining the role of estrogen receptor beta in triple negative breast cancer

Award Number: R01CA251545
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Triple negative breast cancers (TNBCs) do not express estrogen receptor-α (ERα), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2), and therefore, none of the targeted drugs currently in use for breast cancer are effective against them. Approximately 60-80% of TNBCs express estrogen receptor-β (ERβ). However, pro- versus anti-tumorigenic capabilities of ERβ remains controversial. Another key molecular characteristic of TNBC is the high frequency (80%) of p53 mutation. In addition to losing tumor suppressor properties and exerting dominant-negative regulation over any remaining wild type p53 (WTp53), mutant p53 also acquires oncogenic gain-of-function. Increasing evidence suggests that not all mutant p53s function similarly. Although ERβ and p53 have been implicated in TNBC pathology, whether p53 has a role in the pro- versus anti-proliferative functional duality of ERβ remains an open question. The long-term goal is to understand and exploit the role of ERβ-p53 crosstalk in breast cancer for the development of better therapeutic strategies. The objective is to study how specific mutations in p53 impinges upon ERβ function in TNBC, with the prediction that specific p53 mutation will determine its role in the ERβ-mutant p53-p73 signaling axis impacting multiple aspects of tumor progression and metastasis. The hypothesis is that ERβ binds to and inhibits both WTp53 and mutant p53, leading to opposite effects on progression and therapeutic response of TNBC to agents such as Tamoxifen (Tam). The rationale for the proposed research is that understanding how ERβ elicits opposite functions in a p53 status-dependent manner will be critical to stratify TNBC patients to repurpose established therapeutic agents such as Tam to treat large percentage of TNBC patients. The specific aims are: (1 Determine the interaction of different p53 mutants with p73 and ERβ in TNBC cells; (2) Analyze the differential effects of p53 mutants on tumor progression, metastasis and therapeutic response in vivo; and (3) Evaluate the clinical significance of the ERβ-p53-p73 signaling axis. In specific aim 1, Isogenic TNBC cells expressing different combinations of ERβ and WT and p53 mutants generated using CRISPR technology and shRNA-mediated conditional knockdown will be used for analyzing the mechanisms underlying the interaction and its impact on cellular functions in vitro and tumor progression in vivo. In specific aim 2, the effect of different p53 mutations on tumor growth and metastasis will be analyzed in vivo. The clinical relevance of these studies will be evaluated using well-characterized patient derived xenografts (PDXs); patient tumor-derived organoids (PDOs); and patient tumor tissues with linked clinical database (specific aim 3). The contribution of this research is expected to be better understanding of the mechanisms by which ERβ-p53-p73 axis in the context of different p53 mutations affects the disease progression and therapeutic response. The proposal is innovative because analyzing the differential effects of different p53 mutations as part of an integrated ERβ-mutant p53-p73 signaling axis is a departure from the status quo and has the potential of developing novel therapeutic strategies against TNBC.


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: 2024 ( Subtotal = $579,696 )
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$30,510
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	4	2/13/2024	NON-COMPETING CONTINUATION	$549,186
														Subtotal = $579,696

Issue Date FY: 2023 ( Subtotal = $591,642 )
2023	2023	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	3	2/23/2023	NON-COMPETING CONTINUATION	$591,642
														Subtotal = $591,642

Issue Date FY: 2022 ( Subtotal = $599,304 )
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	2	2/21/2022	NON-COMPETING CONTINUATION	$550,378
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	001	2	5/9/2022	NON-COMPETING CONTINUATION	$48,926
														Subtotal = $599,304

Issue Date FY: 2021 ( Subtotal = $566,906 )
2021	2021	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	1	2/24/2021	NEW	$566,906
														Subtotal = $566,906

Grand Total All Awards = $2,337,548

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Functional Significance of individual p53 mutations in determining the role of estrogen receptor beta in triple negative breast cancer

Award Number: R01CA251545

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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