Wednesday, February 5, 2025 2/5/2025

Mechanistic Links Between Changing Estrogen Profiles, Inflammation and the Increased Risk and Metastasis of Breast Cancer in Obese Women

Award Number: R01CA210440
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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View Award Abstract

Obesity prevalence is >39% in the USA. Obesity increases estrone synthesis in fat; and both obesity and estrone correlate with increased postmenopausal ER+ breast cancer risk and mortality. We aim to elucidate how estrone links obesity, inflammation and breast cancer. Obese fat is chronically inflamed via NFB activation. We found breast fat inflammation increases with obesity, after menopause and surrounding cancers. Breast cancer:adipocyte contact upregulates proinflammatory cytokines that stimulate NFB- and estrone:ER-dependent cancer stem cell (CSC) expansion. We showed the dominant premenopausal estradiol (E2) and postmenopausal estrone (E1) regulate different genes. While E2-bound ER inhibits NFB, we showed E1-bound ER is an NFB co-activator and induces gene profiles of inflammation, EMT, CSC expansion and metastasis, while E2 did not. Finally, E1: ER caused more cytokine gene induction, stem cell expansion, and ER+ tumor growth and metastasis than E2 in vivo. While our in vivo data suggest E1 driven ER-NFB co-targets promote tumor progression, little is known about how E1-bound ER and NFB interact at chromatin, and how their co-regulators differ from those of E2-ER. Up to 30% of metastatic ER+ BC develop activating ESR1 mutations. We found while 3D growth of MCF7 controls is greater with E1 than E2; both stimulate 3D growth of ER mutant MCF7 lines equally. Further, both ER mutants direct greater NFB activation upon either E1 or E2 treatment, suggesting that the altered mutant ER conformation might direct greater ER-p65B activation. We hypothesize that E1-ER target gene selection, co-regulators, and expression differ from those of E2:ER and that therapy-induced ER mutants will permit pro-inflammatory, oncogenic, and prometastatic ER-NFB target genes, normally activated only by E1-bound ER-WT, to be indiscriminately activated by either E1 or E2 in cancers. Aim 1 will test how E1 and E2 driven gene expression differs, comparing ChIPseq of ER, p65B and FOXA1 and correlating these with gene expression profiles in ER+ cancer lines and organoids stimulated by E1 vs E2, +/- NFB. Aim 2 To identify co-regulators unique to E1 and E2-liganded ER that mediate gene induction or repression, we carry out i) ChIP-Mass Spec in cells treated with E1 or E2, +/- NFB activation; and ii) Gradient-Seq to separate euchromatin from heterochromatin followed by ChIPseq and ChIP-Mass Spec to identify the E1- vs E2-liganded ER interactome in transactivator versus repressor complexes. Aim 3 will test if both E1 and E2 i) cause greater ER:p65 binding and ii) preferential activation of oncogenic ER mutant: B co-target genes normally activated by E1-liganded ER-WT +/-NFB in vitro, and ii) activate a more E1-ER-like oncogenic genes profile in ERY537S BC xenografts and PDX than in ER-WT BC tumors in vivo. This will inform how ER target gene changes during the shift from high E2 to high E1 after menopause might promote breast cancer development and may identify new therapeutic targets, ultimately yielding new ER+ breast cancer therapies and prevention strategies.


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 = $375,941 )
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	9	11/26/2024	NON-COMPETING CONTINUATION	$375,941
														Subtotal = $375,941

Issue Date FY: 2024 ( Subtotal = $395,178 )
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	8	11/20/2023	NON-COMPETING CONTINUATION	$374,379
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	002	8	4/17/2024	NON-COMPETING CONTINUATION	$20,799
2024	2023	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	001	7	11/22/2023	COMPETING CONTINUATION	$0
														Subtotal = $395,178

Issue Date FY: 2023 ( Subtotal = $415,197 )
2023	2023	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	7	11/23/2022	COMPETING CONTINUATION	$382,523
2023	2023	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	001	7	3/14/2023	COMPETING CONTINUATION	$32,674
2023	2021	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	002	6	5/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $415,197

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	6	8/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $351,133 )
2021	2021	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	002	6	2/26/2021	NON-COMPETING CONTINUATION	$351,133
2021	2020	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	001	5	11/6/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$678
2021	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	000	4	11/6/2020	NON-COMPETING CONTINUATION	-$678
														Subtotal = $351,133

Issue Date FY: 2020 ( Subtotal = $351,131 )
2020	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	000	4	2/14/2020	NON-COMPETING CONTINUATION	$351,131
2020	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	001	4	7/29/2020	NON-COMPETING CONTINUATION	-$277,287
2020	2020	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	002	5	7/29/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$277,287
														Subtotal = $351,131

Issue Date FY: 2019 ( Subtotal = $340,596 )
2019	2019	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	000	3	2/15/2019	NON-COMPETING CONTINUATION	$340,596
														Subtotal = $340,596

Issue Date FY: 2018 ( Subtotal = $476,131 )
2018	2018	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	000	2	2/6/2018	NON-COMPETING CONTINUATION	$316,017
2018	2018	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	2	7/19/2018	SUPPLEMENT FOR EXPANSION	$125,000
2018	2018	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	001	2	5/21/2018	NON-COMPETING CONTINUATION	$35,114
														Subtotal = $476,131

Issue Date FY: 2017 ( Subtotal = $351,131 )
2017	2017	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	000	1	3/7/2017	NEW	$351,131
														Subtotal = $351,131

Grand Total All Awards = $3,056,438

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Mechanistic Links Between Changing Estrogen Profiles, Inflammation and the Increased Risk and Metastasis of Breast Cancer in Obese Women

Award Number: R01CA210440

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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