miR-221/222 control luminal breast cancer tumor progression by regulating different targets

alpha 6 beta 4 integrin is an adhesion molecule for laminin receptors involved in tumor progression. We present a link between beta 4 integrin expression and miR-221/222 in the most prevalent human mammary tumor: luminal invasive carcinomas (Lum-ICs). Using human primary tumors that display different beta 4 integrin expression and grade, we show that miR-221/222 expression inversely correlates with tumor proliferating index, Ki67. Interestingly, most high-grade tumors express beta 4 integrin and low miR-221/222 levels. We ectopically transfected miR-221/222 into a human-derived mammary tumor cell line that recapitulates the luminal subtype to investigate whether miR-221/222 regulates beta 4 expression. We demonstrate that miR-221/222 overexpression results in beta 4 expression downregulation, breast cancer cell proliferation, and invasion inhibition. The role of miR-221/222 in driving beta 4 integrin expression is also confirmed via mutating the miR-221/222 seed sequence for beta 4 integrin 3'UTR. Furthermore, we show that these 2 miRNAs are also key breast cancer cell proliferation and invasion regulators, via the post-transcriptional regulation of signal transducer and activator of transcription 5A (STAT5A) and of a disintegrin and metalloprotease-17 (ADAM-17). We further confirm these data by silencing ADAM-17, using a dominant-negative or an activated STAT5A form. miR-221/222-driven beta 4 integrin, STAT5A, and ADAM-17 did not occur in MCF-10A cells, denoted normal breast epithelial cells, indicating that the mechanism is cancer cell-specific. These results provide the first evidence of a post-transcriptional mechanism that regulates beta 4 integrin, STAT5A, and ADAM-17 expression, thus controlling breast cancer cell proliferation and invasion. Pre-miR-221/222 use in the aggressive luminal subtype may be a powerful therapeutic anti-cancer strategy.