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

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 influ...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266002/
https://www.ncbi.nlm.nih.gov/pubmed/37252969
http://dx.doi.org/10.1073/pnas.2122053120
Descripción
Sumario: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.