Regulation of hormone signaling by nuclear receptor interacting proteins.

Abstract : Nuclear receptors are ligand-activated transcription factors which regulate the expression of genes critical for the growth of hormone-dependent cancers. Their expression and activity are controlled by various cofactors which are important players in hormone-dependent carcinogenesis. RIP140 is a negative transcriptional regulator which is recruited by agonist-liganded receptors. Its strong repressive activity involves four silencing domains which interact with histone deacetylases (HDACs), carboxyl-terminal binding proteins (CtBPs) and additional partners. RIP140 positively regulates transactivation when nuclear receptors are recruited to target promoters through interaction with the Sp1 transcription factor. In human breast cancer cells, RIP140 expression is upregulated at the transcriptional level by various ligands of nuclear receptors revealing the existence of regulatory loops. The Mdm2 oncogenic ubiquitin-ligase is another protein which directly interacts with nuclear receptors. It is involved in a ternary complex with ERΑ and p53 and regulates ERΑ turn-over. In MCF-7 human breast cancer cells, various p53-inducing agents (such as UV irradiation) abolished E2-dependent turn-over of ERΑ without affecting its transactivation potential. Altogether, our results show that RIP140 and Mdm2 are two important regulators of ERΑ expression and activity and could therefore play major roles in hormone-dependent breast carcinogenesis.