14-3-3ζ Turns TGF-β's Function from Tumor Suppressor to Metastasis Promoter in Breast Cancer by Contextual Changes of Smad Partners from p53 to Gli2

Transforming growth factor beta (TGF-beta) functions as a tumor suppressor in premalignant cells but as a metastasis promoter in cancer cells. The dichotomous functions of TGF-beta 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 zeta destabilizes p53, a Smad partner in premalignant mammary epithelial cells, by downregulating 14-3-3 sigma, thus turning off TGF-beta's tumor suppression function. Conversely, 14-3-3 zeta stabilizes Gli2 in breast cancer cells, and Gli2 partners with Smads to activate PTHrP and promote TGF-beta-induced bone metastasis. The 14-3-3 zeta-driven contextual changes of Smad partners from p53 to Gli2 may serve as biomarkers and therapeutic targets of TGF-beta-mediated cancer progression.