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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2023-06, Vol.120 (23), p.e2122053120-e2122053120
• Main Authors: Drula, Rares, Pardini, Barbara, Fu, Xiao, De Los Santos, Mireia Cruz, Jurj, Ancuta, Pang, Lan, El-Daly, Sherien M, Fabris, Linda, Knutsen, Erik, Dragomir, Mihnea P, Bayraktar, Recep, Li, Yongfeng, Chen, Meng, Del Vecchio, Filippo, Berland, Léa, Dae, Jessica, Fan, Daniel, Shimizu, Masayoshi, Tran, Anh M, Barzi, Mercedes, Pioppini, Carlotta, Gutierrez, Angelica M, Ivan, Cristina, Meas, Salyna, Hall, Carolyn S, Alahari, Suresh K, Berindan-Neagoe, Ioana, Fabbri, Muller, Lucci, Anthony, Arun, Banu, Anfossi, Simone, Calin, George A
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Biological Sciences; Biosynthesis; Breast cancer; Breast Neoplasms - pathology; Down-regulation; Estradiol - metabolism; Estradiol - pharmacology; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Estrogens - metabolism; Extracellular Vesicles - genetics; Extracellular Vesicles - metabolism; Female; Humans; Macrophages; Malignancy; Microenvironments; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Ribonucleic acid; RNA; Sex hormones; Tumor Microenvironment; Tumor suppressor genes; Tumors
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2122053120

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.