The Dichotomous Functions of TGFβ in Breast Cancer Are Regulated by 14-3-3ζ

TGFβ plays a complex role in cancer development, switching from a tumor suppressor in premalignant cells to a metastatic driver in cancer cells; however, the mechanisms that regulate this switch in TGFβ function are poorly understood. Activation of TGFβ signaling is known to involve the assembly of SMAD transcription factor complexes, but it remains unclear whether specific SMAD binding partners regulate the context-specific functions of TGFβ during tumor progression. Xu and colleagues found that overexpression of 14-3-3ζ, which promotes TGFβ activity and cell transformation, in nontransformed mammary epithelial cells led to bypass of TGFβ-induced growth inhibition by repressing 14-3-3σ–mediated stabilization of the SMAD partner p53 and preventing downstream p21 activation. Mechanistically, 14-3-3ζ suppressed 14-3-3σ transcription by sequestering the transcriptional activator YAP1 in the cytoplasm and inhibiting its recruitment to the 14-3-3σ promoter. Furthermore, suppression of 14-3-3ζ in metastatic TGFβ-responsive breast cancer cells inhibited the expression of a subset of genes that have previously been associated with breast cancer bone metastasis, suggesting that 14-3-3ζ may shift TGFβ's function from a tumor suppressor to a metastatic driver by altering SMAD partner availability. In support of this idea, 14-3-3ζ promoted TGFβ-induced bone metastasis in mice by stabilizing the SMAD partner GLI2 via inhibition of its interaction with β-transducin repeat–containing E3 ubiquitin ligase, resulting in increased transcription of the gene encoding parathyroid hormone–related protein and enhanced osteoclast maturation. Clinically, expression of 14-3-3ζ and GLI2 increased during breast cancer progression, whereas levels of nuclear YAP1, 14-3-3σ, and p21 were decreased. Together, this work indicates that 14-3-3ζ regulates TGFβ function by shifting SMAD binding partners from p53 to GLI2 during cancer progression and provides a rationale for the use of GLI2 as a potential therapeutic target and biomarker to predict cancers that are likely to respond to TGFβ-targeted therapy.

Xu J, Acharya S, Sahin O, Zhang Q, Saito Y, Yao J, et al. 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. Cancer Cell 2015;27:177–92.