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

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2024 · $395,178

## 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 NFκB
activation. We found breast fat inflammation increases with obesity, after menopause and surrounding
cancers. Breast cancer:adipocyte contact upregulates proinflammatory cytokines that stimulate NFκB- and
estrone:ERα-dependent cancer stem cell (CSC) expansion. We showed the dominant premenopausal
estradiol (E2) and postmenopausal estrone (E1) regulate different genes. While E2-bound ERα inhibits NFκB,
we showed E1-bound ERα is an NFκB co-activator and induces gene profiles of inflammation, EMT, CSC
expansion and metastasis, while E2 did not. Finally, E1: ERα 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-NFκB co-targets promote tumor progression, little is known about how E1-bound ER and NFκB 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 NFκB
activation upon either E1 or E2 treatment, suggesting that the altered mutant ER conformation might direct
greater ER-p65κB activation. We hypothesize that E1-ERα target gene selection, co-regulators, and
expression differ from those of E2:ERα and that therapy-induced ERα mutants will permit pro-inflammatory,
oncogenic, and prometastatic ERα-NFκB 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, p65κB and FOXA1 and correlating these with gene expression profiles in
ER+ cancer lines and organoids stimulated by E1 vs E2, +/- NFκB. Aim 2 To identify co-regulators unique to
E1 and E2-liganded ERα that mediate gene induction or repression, we carry out i) ChIP-Mass Spec in cells
treated with E1 or E2, +/- NFκB activation; and ii) Gradient-Seq to separate euchromatin from heterochromatin
followed by ChIPseq and ChIP-Mass Spec to identify the E1- vs E2-liganded ERα 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: κB co-target genes normally activated by E1-liganded ER-WT
+/-NFκB 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:** 10745726
- **Project number:** 5R01CA210440-08
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** JOYCE MARIE SLINGERLAND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $395,178
- **Award type:** 5
- **Project period:** 2017-03-07 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745726

## Citation

> US National Institutes of Health, RePORTER application 10745726, Mechanistic Links Between Changing Estrogen Profiles, Inflammation and the Increased Risk and Metastasis of Breast Cancer in Obese Women (5R01CA210440-08). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10745726. Licensed CC0.

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