GATA3 transcription factor abrogates Smad4 transcription factor-mediated fascin overexpression, invadopodium formation, and breast cancer cell invasion.

ABSTRACT

Transforming growth factor ß (TGFß) is a potent and context-dependent regulator of tumor progression. TGFß 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 TGFß-Smad4 signaling pathway in basal-like breast cancer cells. TGFß and Smad4 induced fascin overexpression by directly binding to a Smad binding element on the fascin promoter. We identified GATA3, a transcription factor crucial for mammary gland morphogenesis and luminal differentiation, as a negative regulator of TGFß- and Smad4-induced fascin overexpression. When ectopically expressed in basal-like breast cancer cells, GATA-3 abrogated TGFß- and Smad4-mediated overexpression of fascin and other TGFß response genes, invadopodium formation, cell migration, and invasion, suggesting suppression of the canonical TGFß-Smad signaling axis. Mechanistically, GATA3 abrogated the canonical TGFß-Smad signaling by abolishing interactions between Smad4 and its DNA binding elements, potentially through physical interactions between the N-terminal of GATA3 and Smad3/4 proteins. Our findings provide mechanistic insight into how TGFß-mediated cell motility and invasiveness are differentially regulated in breast cancer.