Abstract LB-202: 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

TGF-β manifests multifunctional and dichotomous roles in different stages of cancer progression. In premalignant cells, TGF-β is primarily a tumor suppressor that inhibits cell proliferation or induces apoptosis. In the later stages of cancer progression, however, TGF-β functions as a metastasis promoter by inducing epithelial-mesenchymal transition (EMT), leading to increased invasion of cancer cells, and also by inducing genes that facilitate metastatic colonization of secondary organ sites. Although the opposing functions of TGF-β in early- versus late-stage cancer have been known for decades, how and when TGF-β switches its functional roles are long-standing questions with no clear answer. It has been postulated that the dichotomous functions of TGF-β are dictated by different partners of its downstream Smads. However, it is unclear how Smad partners are changed in different stages of cancer. We have investigated how Smad partners are changed in different stages of breast cancer development in 2D and 3D cell cultures by both hypothesis-driven and unbiased approaches, in mouse models of bone metastasis, by bioinformatics analysis of breast cancer TCGA data, and by immunohistochemistry analysis of different stages of human breast diseases/cancers. Together, our data demonstrated that 14-3-3ζ overexpression induces contextual changes of Smad partners. Specifically, 14-3-3ζ 1) switches off TGF-β9s cytostatic tumor suppressor function during the early stage (ADH) of breast cancer development by cytoplasmic sequestration of YAP1, leading to reduced 14-3-3σ transcription, which results in destabilization of p53, a Smad determinant for p21 transactivation in pre-malignant cells, and consequently decreased p21 expression; 2) switches on TGF-β9s metastasis promoter function during breast cancer progression (DCIS/IDC) by blocking Gli2 binding with its E3 ligase β-TrCP, thus stabilizing Gli2, a Smad determinant for PTHrP transactivation in cancer cells, leading to bone metastasis (Cancer Cell, In Press, 2015). The critical role of TGF-β in cancer, especially in the process of metastasis, has spurred the development of TGF-β-targeting agents as cancer therapeutics. Disappointingly, many of the current TGF-β-targeting drugs showed limited clinical efficacy. Considering the opposing functions of TGF-β in cancer development, general inhibition of the TGF-β pathway may have deleterious consequence. Based on our new findings, the 14-3-3ζ-driven contextual changes of Smad partners from p53 to Gli2 may serve as a) biomarkers and b) therapeutic targets of TGF-β-mediated cancer progression and metastasis. Citation Format: Jia Xu, Sunil Acharya, Ozgur Sahin, Lin Zhang, Frank J. Lowery, Aysegul A. Sahin, Xiang H.-f. Zhang, Mien-Chie Hung, Dihua Yu. 14-3-3ζ turns TGF-β9s function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-202. doi:10.1158/1538-7445.AM2015-LB-202