Smad3 plays an important role in inhibiting cell proliferation and promoting apoptosis in multiple tissues, including the breast tissue. At late stages, Smad3 promotes breast cancer progression and metastasis. We previously showed that the proline-rich linker region of Smad3 is phosphorylated by several kinases, such as by CDKs and MAP kinases. We have mapped these phosphorylation sites. We show that mutation of the phosphorylation sites in the Smad3 linker region increases the ability of Smad3 to inhibit cell proliferation and promote apoptosis. Interestingly, mutation of the Smad3 linker phosphorylation sites also increases the ability of Smad3 to activate genes that promote metastasis. Accordingly, mutation of the Smad3 linker phosphorylation sites markedly inhibits tumorigenicity but promotes metastasis of breast cancer cell lines. Using human breast cancer tissue microarrays, we further show that Smad3 linker phosphorylation is progressively reduced along breast cancer progression. Taken together, our findings strongly suggest that Smad3 linker phosphorylation promotes tumorigenesis but inhibits metastasis. Our findings have important implications for cancer therapy.
Date:
2015-08
Relation:
Cancer Research. 2015 Aug;75(Suppl. 15):Abstract number 4940.
