TY - JOUR
T1 - 17β-estradiol promotes extracellular vesicle release and selective miRNA loading in ERα-positive breast cancer
AU - Drula, Rares
AU - Pardini, Barbara
AU - Fu, Xiao
AU - De los Santos, Mireia Cruz
AU - Jurj, Ancuta
AU - Pang, Lan
AU - El-Daly, Sherien M.
AU - Fabris, Linda
AU - Knutsen, Erik
AU - Dragomir, Mihnea P.
AU - Bayraktar, Recep
AU - Li, Yongfeng
AU - Chen, Meng
AU - Del Vecchio, Filippo
AU - Berland, Léa
AU - Dae, Jessica
AU - Fan, Daniel
AU - Shimizu, Masayoshi
AU - Tran, Anh M.
AU - Barzi, Mercedes
AU - Pioppini, Carlotta
AU - Gutierrez, Angelica M.
AU - Ivan, Cristina
AU - Meas, Salyna
AU - Hall, Carolyn S.
AU - Alahari, Suresh K.
AU - Berindan-Neagoe, Ioana
AU - Fabbri, Muller
AU - Lucci, Anthony
AU - Arun, Banu
AU - Anfossi, Simone
AU - Calin, George A.
N1 - Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
KW - breast cancer
KW - estrogen receptor
KW - exosomes
KW - extracellular vesicles
KW - microRNAs
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U2 - 10.1073/pnas.2122053120
DO - 10.1073/pnas.2122053120
M3 - Article
C2 - 37252969
AN - SCOPUS:85160654454
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 23
ER -