TGFβ-induced c-Myb affects the expression of EMT-associated genes and promotes invasion of ER+ breast cancer cells
Volume 10, Issue 23
Downloads and Tools
December 1, 2011
Pages 4149 - 4161http://dx.doi.org/10.4161/cc.10.23.18346
Authors: Vincenzo Cesi, Arianna Casciati, Fabiola Sesti, Barbara Tanno, Bruno Calabretta and Giuseppe Raschellà View affiliations
Advanced breast cancer cells acquire metastatic properties in response to TGFβ. We show here that the expression of c-Myb increases in TGFβ-treated ER+ breast cancer cells by protein stabilization, transcription activation and release from miR200-dependent down-regulation. In particular, we mapped 2 sites for miR200b, miR200c and miR429 binding in the 3’ UTR of the human c-myb gene. These microRNAs decreased the expression of c-Myb when transfected in MCF-7 cells. In addition, luciferase activity from a vector containing the 3’ UTR of the c-myb gene was inhibited by miR200s through a binding-dependent mechanism. siRNA- and shRNA-mediated down-regulation was used to investigate the role of c-Myb for the effects induced by TGFβ in ER+ breast cancer MCF-7 and ZR-75.1 cells. Transfection with c-Myb siRNAs blocked the increase of Slug (SNAI2) and Bcl-2 expression and reversed the decrease in E-cadherin expression induced by TGF−β treatment. Conversely, c-Myb down-regulation decreased invasion and anchorage-independent growth of breast cancer cells expressing a constitutively active TGFβ receptor I. Finally, apoptosis induced by etoposide increased in c-Myb-silenced TGFβ−treated ER+ cell lines. In summary, exposure of ER+ breast cancer cells to TGFβ induces an increase of c-Myb expression which is required for expression of EMT-associated markers, in vitro invasion and anchorage-independent growth. Furthermore, our findings suggest a potentially detrimental effect of TGFβ and c-Myb co-expression in breast cancer.
Received: September 21, 2011; Accepted: October 7, 2011