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GPER1-dependent regulation of IGF-1R in tamoxifen treated breast cancer cells

Award Number: SC1GM127175
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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GPER1-dependent regulation of IGF-1R in tamoxifen treated breast cancer cells - The majority of breast cancers express estrogen receptor alpha (ER) and are estrogen-dependent. In ER- positive breast cancer, ER antagonists decrease cell proliferation and tumor growth. Tamoxifen (Tam), an ER antagonist in breast cancer cells, is the most widely used adjuvant therapy for patients diagnosed with ER-positive breast cancer. While Tam treatment is effective for most patients, innate Tam resistance is observed in some patients and the development of Tam resistance after long-term treatment remains a clinically relevant outcome. The molecular mechanisms that underlie Tam resistance are not well understood. While Tam action is often attributed entirely to ER antagonism, Tam sensitivity has been observed in breast cancer cells that lack ER suggesting alternative mechanisms of Tam action. We have shown that GPER1 mediates Tam action in breast cancer cells via induction of IGFBP-1 expression and subsequent inhibition of IGF-1R-dependent cell signaling. Additionally, our data indicate that this GPER1-mediated mechanism of Tam action inhibits IGF-1-stimulated ER phosphorylation. The role of IGFBPs during Tam treatment and the development of Tam resistance has not been adequately studied. GPER1-mediated mechanisms of Tam action in breast cancer cells modulate IGF-1R activity and inhibit phosphorylation-dependent ER signaling. To test this hypothesis, three independent Aims are proposed. Included in all three Aims are experiments utilizing a panel of breast cancer cell lines to model Tam efficacy in multiple breast cancer subtypes. Completion of these aims will result in (1) Defining the role of IGFBP family members during Tam treatment, (2) Elucidating GPER1-mediated mechanisms that inhibit phosphorylation-dependent ER activity in Tam- treated breast cancer cells, and (3) Determine the IGFBP-dependent molecular mechanisms that drive Tam resistance via modulation of growth factor signaling. Upon completion of these Aims, our knowledge regarding the molecular mechanisms of GPER1-mediated Tam action in breast cancer cells will be significantly increased and the molecular mechanisms of the role of GPER1 during the development of Tam resistance will be more clearly defined. Data obtained from these experiments will provide new models of understanding Tam action for future animal model and clinical studies of this commonly used therapeutic.


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 = -$918 )
2025	2022	NEW MEXICO STATE UNIVERSITY	1050 STEWART ST.	LAS CRUCES	NM	88003	DONA ANA	USA	Biomedical Research and Research Training	000	4	5/6/2025	NON-COMPETING CONTINUATION	-$918
														Subtotal = -$918

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	NEW MEXICO STATE UNIVERSITY	1050 STEWART ST.	LAS CRUCES	NM	88003	DONA ANA	USA	Biomedical Research and Research Training	000	4	12/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $370,000 )
2022	2022	NEW MEXICO STATE UNIVERSITY	1050 STEWART ST STE E1200	LAS CRUCES	NM	88003	DONA ANA	USA	Biomedical Research and Research Training	001	4	6/14/2022	NON-COMPETING CONTINUATION	$37,000
2022	2022	NEW MEXICO STATE UNIVERSITY	1050 STEWART ST STE E1200	LAS CRUCES	NM	88003	DONA ANA	USA	Biomedical Research and Research Training	000	4	12/14/2021	NON-COMPETING CONTINUATION	$333,000
														Subtotal = $370,000

Issue Date FY: 2021 ( Subtotal = $370,000 )
2021	2021	NEW MEXICO STATE UNIVERSITY	1050 STEWART ST STE E1200	LAS CRUCES	NM	88003	DONA ANA	USA	Biomedical Research and Research Training	000	3	12/22/2020	NON-COMPETING CONTINUATION	$333,000
2021	2021	NEW MEXICO STATE UNIVERSITY	1050 STEWART ST STE E1200	LAS CRUCES	NM	88003	DONA ANA	USA	Biomedical Research and Research Training	001	3	2/17/2021	NON-COMPETING CONTINUATION	$37,000
														Subtotal = $370,000

Issue Date FY: 2020 ( Subtotal = $370,000 )
2020	2020	NEW MEXICO STATE UNIVERSITY	1050 STEWART ST STE E1200	LAS CRUCES	NM	88003	DONA ANA	USA	Biomedical Research and Research Training	000	2	1/8/2020	NON-COMPETING CONTINUATION	$370,000
														Subtotal = $370,000

Issue Date FY: 2019 ( Subtotal = $370,000 )
2019	2019	NEW MEXICO STATE UNIVERSITY	1050 STEWART ST STE E1200	LAS CRUCES	NM	88003	DONA ANA	USA	Biomedical Research and Research Training	000	1	12/31/2018	NEW	$370,000
														Subtotal = $370,000

Grand Total All Awards = $1,479,082

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GPER1-dependent regulation of IGF-1R in tamoxifen treated breast cancer cells

Award Number: SC1GM127175

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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