14-3-3? turns TGF-?'s function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2.

ABSTRACT: Transforming growth factor ? (TGF-?) functions as a tumor suppressor in premalignant cells but as a metastasis promoter in cancer cells. The dichotomous functions of TGF-? are proposed to be dictated by different partners of its downstream effector Smads. However, the mechanism for the contextual changes of Smad partners remained undefined. Here, we demonstrate that 14-3-3? destabilizes p53, a Smad partner in premalignant mammary epithelial cells, by downregulating 14-3-3?, thus turning off TGF-?'s tumor suppression function. Conversely, 14-3-3? stabilizes Gli2 in breast cancer cells, and Gli2 partners with Smads to activate PTHrP and promote TGF-?-induced bone metastasis. The 14-3-3?-driven contextual changes of Smad partners from p53 to Gli2 may serve as biomarkers and therapeutic targets of TGF-?-mediated cancer progression.

SUBMITTER: Xu J 

PROVIDER: S-EPMC4325275 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature