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

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2023 · $415,197

## 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...

## Key facts

- **NIH application ID:** 10585320
- **Project number:** 2R01CA210440-07A1
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** JOYCE MARIE SLINGERLAND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $415,197
- **Award type:** 2
- **Project period:** 2017-03-07 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10585320

## Citation

> US National Institutes of Health, RePORTER application 10585320, Mechanistic Links Between Changing Estrogen Profiles, Inflammation and the Increased Risk and Metastasis of Breast Cancer in Obese Women (2R01CA210440-07A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10585320. Licensed CC0.

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