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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)

Group Awards By Issue Date FY or Funding FY:

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Project Summary Obesity increases the risk and adverse prognosis of postmenopausal estrogen receptor-positive (ER+) breast cancer. Paradoxically, although estrogens stimulate breast cancers, risk rises markedly after menopause, when estrogens decrease. After menopause, estradiol falls and estrone is produced largely in fat by aromatase. Obesity women have high estrone, and both obesity and high estrone, but not estradiol, increase ER+ breast cancer risk after menopause. Low intra-tumor levels of enzymes converting estrone into estradiol, and elevation of enzymes that produce estrone both confer worse ER+ breast cancer outcome. Obesity mediates chronic inflammation through NF-¿B driven cytokine expression. We showed contact between invading breast cancer cells and obese adipose tissue induces pro-inflammatory cytokines in both cell types that stimulate cancer stem cells (CSC) and drive metastasis. Our data suggest that cytokine induction after breast fat:cancer cell contact is estrogen:ER dependent, since blocking estrogen synthesis with the aromatase inhibitor, letrozole, reduced cytokine induction upon co-culture. While estradiol is known to oppose NF-¿B mediated inflammation, the role of estrone in inflammation is not known and may differ from that of estradiol. We will study how estrone and estradiol, and changes in the ratios thereof before and after- menopause, may influence NF-¿B activity and the pro-inflammatory state in obese postmenopausal women. We hypothesize that increased estrone:estradiol ratio after menopause shifts ER from an NF-¿B co- repressor to a co-activator to up-regulate cytokines in obese adipocytes and cancer cells that drive CSC expansion and metastasis. We also posit that enzymes that convert estradiol to estrone may contribute to the poor outcome of ER+ cancers in obesity. Aim 1 will test if estradiol:ER decreases, estrone:ER increases or different estradiol:estrone ratios alter ER effects on NF-¿B mediated induction of pro-inflammatory cytokine gene drivers of CSCs in ER+ breast cancer cells. To test in Aim 2 if estrone cooperates with obesity to drive ER+ breast cancer initiation and growth, we will co-culture human ER+ breast cancer cells with mammary adipocytes from women with different body mass index (BMI) +/- aromatase inhibition and test consequences on cytokine levels and CSC. We will also implant syngeneic breast cancers into lean or obese wild-type or aromatase knock-out mice to elucidate if host estrone mediates tumor promoting effects of obesity. Aim 3 will test if overexpression of HSD17B14, that converts estradiol to estrone, increases ER+ breast cancer cytokine expression and CSC in vitro, and increases tumor initiation and metastasis in vivo. We will also compare levels of estradiol/estrone interconversion enzymes in breast adipocytes and cancers from lean, overweight and obese women. A better understanding of the roles of estradiol and estrone may lead to new strategies for breast cancer prevention and treatment, and to changes in hormone replacement therapies. Shifting toward a higher estradiol: estrone ratio in serum or in breast cancer cells may prove to have therapeutic potential.


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 = $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 = $2,680,497

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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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