17β-estradiol promotes extracellular vesicle release and selective miRNA loading in ERα-positive breast cancer
Rareş Drulă, Barbara Pardini, Xiao Fu, Mireia Cruz De los Santos, Ancuța Jurj, Lan Pang, Sherien M. El‐Daly, Linda Fabris, Erik Knutsen, Mihnea P. Dragomir, Recep Bayraktar, Yongfeng Li, Meng Chen, Filippo Del Vecchio, Léa Berland, Jessica Dae, Daniel Fan, Masayoshi Shimizu, Anh Minh Tran Huynh, Mercedes Barzi, Carlotta Pioppini, Angelica M. Gutierrez‐Barrera, Cristina Ivan, Salyna Meas, Carolyn Hall, Suresh K. Alahari, Ioana Berindan‐Neagoe, Muller Fabbri, Anthony Lucci, Banu Arun, Simone Anfossi, George A. Călin
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.