Faculty, Staff and Student Publications

Publication Date

6-6-2023

Journal

Proceedings of the National Academy of Sciences of the United States of America

Abstract

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor-positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7's miRNAs into EVs. In multiple patient cohorts, we observed increased levels of let-7a-5p and let-7d-5p in EVs derived from the blood of premenopausal ER+ BC patients, and elevated EV levels in patients with high BMI, both conditions associated with higher levels of 17β-estradiol. In brief, we identified a unique estrogen-driven mechanism by which ER+ BC cells eliminate tumor suppressor miRNAs in EVs, with effects on modulating tumor-associated macrophages in the microenvironment.

Keywords

Humans, Female, MicroRNAs, Breast Neoplasms, Estrogen Receptor alpha, Estradiol, Estrogens, Extracellular Vesicles, Tumor Microenvironment, estrogen receptor, extracellular vesicles, exosomes, breast cancer, microRNAs

DOI

10.1073/pnas.2122053120

PMID

37252969

PMCID

PMC10266002

PubMedCentral® Posted Date

5-30-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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