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Posttranslational Regulation of FOXA1 in Breast Cancer

Award Number: R01CA273444
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Posttranslational Regulation of FOXA1 in Breast Cancer - Project Summary Breast cancer is the second leading cause of cancer mortality in women and nearly 75% of all breast tumors express estrogen receptor alpha (ER) at the time of diagnosis. Despite the therapeutic successes of endocrine therapies designed to target ER function, about 30-40% of tumors become resistant to endocrine therapy, either through de novo or acquired resistance, and still retain the expression of ER. Herein we propose to study the regulation of FOXA1, a pioneer transcription factor that enables ER binding to chromatin, whose theoretical inhibition would circumvent known mechanisms of endocrine therapy resistance. In breast cancer, FOXA1 is responsible for almost all of the ER binding events in the genome and its upregulation is associated with enhancer reprograming in endocrine resistance. However, there is a paucity of information about how FOXA1 itself is regulated and how cancer cells repurpose its pioneering activities to drive oncogenesis. To this end, our lab has been studying the crosstalk between the endocrine and immune systems in breast cancer. We have discovered that FOXA1, in response to the proinflammatory cytokines, is driven to non- canonical sites across the genome to promote chromatin accessibility for estrogen-liganded ER. These newly formed enhancers were found in compacted/latent regions of the genome and promoted the expression of a novel gene set that was predictive of poor clinical outcomes in patients. Concurrently, we discovered that FOXA1 is post-translationally modified (PTM) in response to proinflammatory cytokines at two evolutionarily conserved amino acids. The post-translational modification of FOXA1 in response to external stimuli has not been shown before and suggests an important mechanism that underlies FOXA1 regulation and function. Therefore, the overall goal of this project is to determine the molecular events that allow proinflammatory signaling to alter endocrine signaling through modulation of FOXA1 function and the biological consequences of this crosstalk. We hypothesize that estrogen- and TNFα-directed PTMs of FOXA1 dictate binding site selection, driving ERα to non-canonical enhancers across the genome, leading to expression programs that underlie the tumorigenesis of breast cancer. To systematically test this hypothesis, will use an integrated set of molecular, genomic, and proteomic approaches to: (Aim 1) define the role of FOXA1 PTMs on its pioneering function and chromatin occupancy, (Aim 2) identify the writers and readers of FOXA1 PTMs, and (Aim 3) understand inflammation- based modulation of FOXA1 independent of PTMs. We will perform these experiments in breast cancer cell lines, ER+ patient-derived xenografts (PDX), and in ER+ mature luminal cells isolated from patient tumors. The dependence on FOXA1 for hormone receptor signaling makes it an attractive therapeutic target. While there are currently no known inhibitors of FOXA1 and its protein structure makes it difficult to target therapeutically, our ability to understand basic molecular mechanisms is directly correlated with our ability to develop better therapeutic interventions. Defining how FOXA1 is regulated becomes key to this endeavor.


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: 2025 ( Subtotal = $365,705 )
2025	2025	CENTRO COMPRENSIVO DE CANCER DE LA UNIVERSIDAD DE PUERTO RICO	JOSE C BRBOSA ST CTR	SAN JUAN	PR	00935	SAN JUAN	USA	Cancer Biology Research	002	4	12/19/2024	NON-COMPETING CONTINUATION	$329,134
2025	2025	CENTRO COMPRENSIVO DE CANCER DE LA UNIVERSIDAD DE PUERTO RICO	JOSE C BRBOSA ST CTR	SAN JUAN	PR	00935	SAN JUAN	USA	Cancer Biology Research	004	4	6/5/2025	NON-COMPETING CONTINUATION	$36,571
2025	2025	CENTRO COMPRENSIVO DE CANCER DE LA UNIVERSIDAD DE PUERTO RICO	JOSE C BRBOSA ST CTR	SAN JUAN	PR	00935	SAN JUAN	USA	Cancer Biology Research	003	4	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	000	2	12/4/2024	NON-COMPETING CONTINUATION	-$67,649
2025	2023	CENTRO COMPRENSIVO DE CANCER DE LA UNIVERSIDAD DE PUERTO RICO	JOSE C BRBOSA ST CTR	SAN JUAN	PR	00935	SAN JUAN	USA	Cancer Biology Research	001	3	12/4/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$67,649
														Subtotal = $365,705

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	CENTRO COMPRENSIVO DE CANCER DE LA UNIVERSIDAD DE PUERTO RICO	JOSE C BRBOSA ST CTR	SAN JUAN	PR	00935	SAN JUAN	USA	Cancer Biology Research	001	3	2/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$306,039
2024	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	000	2	2/5/2024	NON-COMPETING CONTINUATION	-$306,039
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $460,474 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	000	2	8/7/2023	NON-COMPETING CONTINUATION	$460,474
														Subtotal = $460,474

Issue Date FY: 2022 ( Subtotal = $478,930 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	000	1	7/26/2022	NEW	$478,930
														Subtotal = $478,930

Grand Total All Awards = $1,305,109

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Posttranslational Regulation of FOXA1 in Breast Cancer

Award Number: R01CA273444

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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