Transforming growth factor β (TGFβ) is a potent and context dependent regulator of tumor progression. TGFβ promotes the lung metastasis of basal-like (but not the luminal-like) breast cancer. Here, we demonstrated that fascin, a pro-metastasis actin bundling protein, was a direct target of the canonical TGFβ-Smad4 signaling pathway in basal-like breast cancer cells. TGFβ and Smad4 induced fascin overexpression by directly binding to a Smad binding element on the fascin promoter. Through data mining, we identified GATA3, a transcription factor crucial for mammary gland morphogenesis and luminal differentiation, as a potential regulator of fascin overexpression. When ectopically expressed in basal-like breast cancer cells, GATA-3 abrogated Smad4-mediated overexpression of fascin and other TGFβ response genes, invadopodium formation, cell migration and invasion, suggesting suppression of the canonical TGFβ-Smad4 signaling axis. Mechanistically, GATA3 might abrogate TGFβ and Smad4-mediated fascin overexpression by abolishing the interactions between Smad4 and its DNA binding elements, potentially through physical interactions between GATA3 and Smad3/4. Our findings provide mechanistic insight into how TGFβ-mediated cell motility and invasiveness are differentially regulated in breast cancer.

Citation Format: Jianwei Sun, Huifang He, Smitha Pillai, Srikumar Chellappan, Shengyu Yang. GATA3 abrogates TGFbeta-mediated breast cancer invasion and metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5001. doi:10.1158/1538-7445.AM2014-5001