Tristetraprolin represses estrogen receptor alpha transactivation in breast cancer cells. [Gene Regulation]

April 15th, 2014 by Barrios–Garcia, T., Tecalco–Cruz, A., Gomez–Romero, V., Reyes–Carmona, S., Meneses–Morales, I., Leon–Del–Rio, A.

The estrogen receptor alpha (ERα) mediates the effects of 17β- estradiol (E2) in normal mammary gland and it is a key participant in breast cancer tumor development. ERα transactivation activity is mediated by the synergistic interaction of two domains designated AF1 and AF2. The function of AF2 is to recruit coactivator and corepressor proteins that allow ERα to oscillate between the roles of transcriptional activator and repressor. In contrast, the mechanism responsible for AF-1 transcriptional activity is not completely understood. In this study we identified tristetraproline (TTP) as a novel ERα associated protein. TTP expression in MCF7 cells repressed ERα-transactivation, reduced MCF7 cell proliferation and their ability to form tumors in a mouse model. We show that TTP transcriptional activity is mediated through its recruitment to the promoter region of ERα target genes and its interaction with histone deacetylases, in particular with HDAC1. TTP expression attenuates the coactivating activity of SRC-1 suggesting that exchange between TTP and other coactivators may play an important role in fine-tunning ERα transactivation. These results indicate that TTP acts as a bona-fide ERα corepressor and suggest that this protein may be a contributing factor in the development of E2-dependent tumors in breast cancer.