Role of TGF-ß signaling in uterine carcinosarcoma.

ABSTRACT

Uterine carcinosarcomas (UCS) are rare (3-4%) but highly aggressive, accounting for a disproportionately high (16.4%) mortality among uterine malignancies. Transforming growth factor beta (TGFß) is a multifunctional cytokine that regulates important cellular processes including epithelial-mesenchymal transition (EMT). Existence of biphasic elements and a report demonstrating amplification of TGFß at 19q13.1 prompted us to investigate the role of TGFß signaling in UCS.Here we demonstrated the components of TGFß pathway are expressed and functional in UCS. TGFß-I induced significant Smad2/3 phosphorylation, migration and EMT responses in UCS cell lines which could be attenuated by the TGFß receptor I (TGFßR-I) or TGFß receptor I/II (TGFßR-I/II) inhibitor developed by Eli Lilly and company. Importantly, TGFß-I induced proliferation was c-Myc dependent, likely through activation of cell cycle. c-Myc was induced by nuclear translocation of nuclear factor of activated T cells (NFAT-1) in response to TGFß-I. Inhibition of NFAT-1 or TGFßR-I blocked c-Myc induction, cell cycle progression and proliferation in UCS. In corroboration, mRNA levels of c-Myc were elevated in recurrent versus the non-recurrent UCS patient samples. Interestingly, in the absence of exogenous TGFß the TGFßR-I/II inhibitor enhanced proliferation likely through non-Smad pathways. Thus, inhibition of TGFßR-I could be efficacious in treatment of UCS.