Smad3 Mediated Mechanisms of Tumor Suppression in Breast Cancer Cells.

摘要

Members of the TGFbeta; superfamily are known to exert a myriad of physiologic and pathologic growth controlling influences on mammary development and oncogenesis. In epithelial cells, TGFbeta; signaling inhibits cell growth through cytostatic and pro-apoptotic activities, but can also induce cancer cell EMT, and thus has a dichotomous role in breast cancer biology. Mechanisms governing this switch are the subject of active investigation. Smad3 is a critical intracellular mediator of TGFbeta; signaling regulated through phosphorylation by the TGFbeta; receptor complex at the C-terminus. Smad3 is also a substrate for several other kinases that phosphorylate additional sites within the Smad protein. This discovery has expanded the understanding of the significance and complexity of TGFbeta; signaling through Smads.;Cyclin D1/CDK4 activity is upregulated in up to 50% of breast cancers and CDK4 mediated phosphorylation negatively regulates Smad3. In the first study, the impact of inhibiting cyclin D1/CDK4 activity, in combination with doxorubicin treatment, on Smad3-mediated cell/colony growth and apoptosis was examined in a cyclin D1 overexpressing model of ER+ breast cancer. The results of this study demonstrated a novel Smad3-regulated mechanism of control over key apoptotic proteins survivin, Smac/DIABLO, and XIAP that was augmented in doxorubicin treated cyclin D overexpressing study cells.;Triple-negative breast cancer represents a particularly aggressive subtype, with overexpression of cyclins D and E being common in this disease. Like cyclin D/CDK4, cyclin E/CDK2 phosphorylates Smad3 through a noncanonical pathway, thereby inhibiting tumor suppressant actions of Smad3. In the second study, the impact of CDK2/4 inhibition on metastatic phenotypes and associated alterations in signaling and protein expression was assessed in triple negative breast cancer cells, along with associated in vivo work using these agents. Altogether, these data showed the potential for specific CDK 2 and 4 inhibitors to impede the metastatic potential of breast cancer cells and supported further investigation of targeted CDK inhibitors as a promising therapeutic strategy for triple-negative breast cancer.;Numerous reports have shown that the microenvironment of human embryonic stem cells is able to reprogram aggressive cancer cells to a less aggressive state by mechanisms that remain ambiguous. In the third study, the phenotypic changes associated with culturing metastatic breast cancer cells in a mouse embryonic stem cell microenvironment were assessed and a transcription factor reporter array was utilized to characterize the signaling pathways associated with these changes. The findings from this work revealed a key role for paradoxical Smad3 within the interaction between the embryonic microenvironment and breast cancer cells.;Collectively, this body of work investigates the critical role of phospho-specific Smad3 in malignancy of the breast and illustrates the potential therapeutic impact of restoring Smad3-mediated tumor suppression in breast cancer.