Hierarchical paracrine interaction of XXXX associated fibroblasts with @entity5 cells via hMAPK-microRNAs to drive ER-negative @entity0 phenotype.

@entity172 @entity558 @entity0 @entity5 @entity494
UNASSIGNED: Multiple juxtacrine and paracrine interactions occur between @entity5 cells and non- @entity5 cells of the @entity5 microenvironment (TME) that direct @entity5 progression. @entity5 Associated Fibroblasts (CAFs) are an integral component of the TME, and the majority of @entity0 stroma is comprised of CAFs. Heterotypic interactions between @entity5 cells and non- @entity5 cells of the TME occur via soluble agents, including cytokines, hormones, growth factors, and secreted microRNAs. We previously identified a microRNA signature indicative of hyperactive MAPK signaling (hMAPK-miRNA signature) that significantly associated with reduced recurrence-free and overall survival. Here we report that the hMAPK-miRNA signature associates with a high metric of stromal cell infiltrate, and we investigate the role of microRNAs, particularly hMAPK-microRNAs, secreted by CAFs on @entity172 receptor (ER) expression in @entity0 cells. ER-positive MCF-7/ltE2- cells were treated with @entity558 ( @entity558 ) from CAFs derived from @entity0 of different PAM50 subtypes (CAFBAS, CAFHER2, and CAFLA). CAF @entity558 isolated specifically from ER-negative primary @entity0 led to ER repression in vitro. Nanoparticle tracking analysis and transmission electron microscopy confirmed the presence of CAF-secreted exosomes in @entity558 and the uptake of these exosomes by the ER+ MCF-7/ltE2- cells. Differentially expressed microRNAs in CAF @entity558 as well as in MCF-7/ltE2- cells treated with this @entity558 were identified. Knockdown of @entity494 /222 in CAFBAS resulted in knockdown of @entity494 /222 levels in the @entity558 and the @entity558 from CAFBAS; @entity494 /222 knockdown rescued ER repression in ER-positive cell lines treated with CAFBAS- @entity558 . Collectively, our results demonstrate that CAF-secreted microRNAs are directly involved in ER-repression, and may contribute to the MAPK-induced ER repression in @entity0 cells.
