Faculty, Staff and Student Publications
Publication Date
6-6-2023
Journal
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.
Keywords
Humans, Female, MicroRNAs, Breast Neoplasms, Estrogen Receptor alpha, Estradiol, Estrogens, Extracellular Vesicles, Tumor Microenvironment, estrogen receptor, extracellular vesicles, exosomes, breast cancer, microRNAs
DOI
10.1073/pnas.2122053120
PMID
37252969
PMCID
PMC10266002
PubMedCentral® Posted Date
5-30-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Genetics Commons, Neoplasms Commons, Oncology Commons