Here we report that tumor promotion by TGF-β in triple negative cancer cells involves not only TMEPAI dependent abrogation of growth suppressive Smad signaling as predicted by TMEPAI-Smad interactions, but also powerful and unsuspected TMEPAI mediated activation of non-canonical signaling through PTEN (phosphatase and tensin homolog) loss and Akt activation. Here, PMEPA1 is linked to neoplasm.