Targeting of the β6 gene to suppress degradation of ECM via inactivation of the MAPK pathway in breast adenocarcinoma cells.

Integrin ανβ6 has emerged as a potential novel target for anticancer and plays a major role in promoting malignant tumor progression. Recent studies indicate that integrin ανβ6 occurs in many cancers. However, whether and how ανβ6 is regulated by genetic and epigenetic mechanisms in breast cancer remain unknown. In the present study, two different short hairpin RNAs (shRNAs) targeting the β6 gene were designed and constructed into pSUPER, respectively, which were transfected into the MCF-7 human breast adenocarcinoma cell line. The β6-shRNA stably transfected cells were successfully established, and significant lower levels of ανβ6 mRNA and protein expression were confirmed. Furthermore, inhibition of integrin ανβ6 markedly downregulated the expression of matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-3 (MMP-3) and urokinase plasminogen activator (uPA) in tumor conditioned medium. Furthermore, β6-shRNA-mediated silencing of the ανβ6 gene obviously decreased the expression of ERK1/2. In particular, supression of integrin ανβ6 caused significant downregulation of the degradation of basement membrane type IV collagen secretion via modulation of the plasminogen activation cascade. Our results thus indicate that ανβ6 plays a fundamental role in promoting invasion and growth of breast adenocarcinoma cells. Taken together, this study revealed that targeting of the β6 gene by RNA interference (RNAi) could efficiently downregulate ανβ6 expression and suppress the ERK1/2-dependent extracellular matrix degradation in vitro, which is dependent upon inactivation of the mitogen-activated protein kinase (MAPK) pathway. These findings may offer a useful therapeutic approach to block invasion and migration of breast cancer cells.