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Investigating the role of G-protein coupled estrogen receptor expression on cancer associated fibroblasts in therapy resistant ER+ breast cancer progression

Award Number: F31CA284785
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/08/2024
PERIOD OF PERFORMANCE END DATE: 04/07/2027

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Investigating the role of G-protein coupled estrogen receptor expression on cancer associated fibroblasts in therapy resistant ER+ breast cancer progression - Project Summary/Abstract Estrogen receptor positive (ER+) breast cancer (BC) accounts for the majority of all diagnosed BC for women in the United States. While traditional antihormone therapies for ER+ BC are initially effective, approximately 40% of ER+ BC will develop therapy resistant recurrence and metastasis, which contributes to most BC related deaths. The presence of the G-protein coupled estrogen receptor (GPER) is suggested to aid in disease progression and metastasis of BC and GPER is theorized to be a driver of therapy resistance due to the agonistic activity of tamoxifen, a traditional antihormone therapy for ER+ BC. GPER is expressed on cancer- associated fibroblasts, the main remodelers of the extracellular matrix (ECM) which plays an important role in disease progression. Previous work by Dr. Suzanne Ponik and collaborators has demonstrated dynamic interactions between hormone signaling and ECM stiffness to drive tumor cell invasion and metastasis. However, the mechanism responsible for these dynamic interactions is poorly understood. Therefore, the hypothesis for the proposed research is that GPER activated CAFs are priming the TME to drive tamoxifen resistant disease progression in ER+ BC. The research strategy proposes to establish the specific role GPER activated CAFs play on ECM protein deposition and organization in vitro prior to introducing GPER knockdown CAFs into an orthotropic ER+, tamoxifen resistant tumor model. The in vitro and in vivo work will be complemented with a novel tumor microarray (TMA) from BC patients where the association between GPER expression, ECM signatures, administered therapy and patient outcome can be validated. The specific aims of this proposal are: 1) identify how GPER signaling in CAFs regulates biophysical/biochemical cues and how GPER-mediated matrix deposition influences tumor cell behavior in vitro, 2) test the hypothesis that ECM stiffness and antihormone therapy synergize through GPER signaling in CAFs to drive tumor progression in vivo, and 3) define how GPER expression and ECM signatures relate to human disease/patient outcomes. The research training for this proposal will be conducted under the co-sponsorship of Dr. Suzanne Ponik (Sponsor) and Dr. Mark Burkard (Co-Sponsor) at the University of Wisconsin-Madison. Both Dr. Ponik and Dr. Burkard will provide mentorship on the research conducted by Shelby Fertal as well as provide guidance for her career development with the intention that Shelby will remain in academia. The success of this proposal will offer novel insights into the mechanisms of antihormone therapy driven disease progression in ER+ BC and provide a solid foundation for Shelby’s career as an independent research professor.


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 = $36,603 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	000	2	4/11/2025	NON-COMPETING CONTINUATION	$36,039
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	001	2	5/28/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $36,603

Issue Date FY: 2024 ( Subtotal = $36,039 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	001	1	4/1/2024	NEW	$0
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	002	1	5/7/2024	NEW	$1,280
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	000	1	4/1/2024	NEW	$34,759
														Subtotal = $36,039

Grand Total All Awards = $72,642

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Investigating the role of G-protein coupled estrogen receptor expression on cancer associated fibroblasts in therapy resistant ER+ breast cancer progression

Award Number: F31CA284785

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/08/2024

PERIOD OF PERFORMANCE END DATE: 04/07/2027

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