17β-estradiol promotes extracellular vesicle release and selective miRNA loading in ERα-positive breast cancer

Rares Drula, University of Texas MD Anderson Cancer Center
Barbara Pardini, Candiolo Cancer Institute-FPO- IRCCS
Xiao Fu, University of Texas MD Anderson Cancer Center
Mireia Cruz De los Santos, University of Texas MD Anderson Cancer Center
Ancuta Jurj, University of Texas MD Anderson Cancer Center
Lan Pang, University of Texas MD Anderson Cancer Center
Sherien M. El-Daly, University of Texas MD Anderson Cancer Center
Linda Fabris, University of Texas MD Anderson Cancer Center
Erik Knutsen, University of Texas MD Anderson Cancer Center
Mihnea P. Dragomir, University of Texas MD Anderson Cancer Center
Recep Bayraktar, University of Texas MD Anderson Cancer Center
Yongfeng Li, University of Texas MD Anderson Cancer Center
Meng Chen, University of Texas MD Anderson Cancer Center
Filippo Del Vecchio, University of Hawaiʻi Cancer Center
Léa Berland, University of Texas MD Anderson Cancer Center
Jessica Dae, University of Texas MD Anderson Cancer Center
Daniel Fan, University of Texas MD Anderson Cancer Center
Masayoshi Shimizu, University of Texas MD Anderson Cancer Center
Anh M. Tran, University of Texas MD Anderson Cancer Center
Mercedes Barzi, Duke University School of Medicine
Carlotta Pioppini, University of Texas MD Anderson Cancer Center
Angelica M. Gutierrez, University of Texas MD Anderson Cancer Center
Cristina Ivan, University of Texas MD Anderson Cancer Center
Salyna Meas, University of Texas MD Anderson Cancer Center
Carolyn S. Hall, University of Texas MD Anderson Cancer Center
Suresh K. Alahari, LSU Health Sciences Center - New OrleansFollow
Ioana Berindan-Neagoe, Universitatea de Medicina si Farmacie Iuliu Hatieganu din Cluj-Napoca
Muller Fabbri, University of Hawaiʻi Cancer Center

Document Type

Article

Publication Date

5-30-2023

Publication Title

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.

PubMed ID

37252969

Volume

120

Issue

23

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