WILLIAM P. SCHIEMANN, PhDAssociate Professor
General Medical Sciences (Oncology)
The process of mammary tumorigenesis and its assortment of associated genetic and epigenetic events enable newly malignant cells to evade the cytostatic activities of TGF-β, which normally functions as a potent antagonist of tumorigenesis. As breast cancer cells continue down the evolutionary path towards advanced malignancy, they ultimately acquire the ability to transform the cytostatic signals produced by TGF-β into oncogenic activities, including enhanced proliferation, invasion, and metastasis. This peculiar conversion in TGF-β function is known as the "TGF-β Paradox," which underlies the lethality of TGF-β in metastatic breast cancers. Moreover, solving the "TGF-β Paradox" and how it initiates the oncogenic activities of TGF-β remains a fundamental question that directly impacts our ability to pharmacologically target the TGF-β signaling system when treating human malignancies, including those of the breast.
The primary goal of our research is to solve the "TGF-β Paradox" and its relationship to the initiation of epithelial-mesenchymal transition, which couples TGF-β to breast cancer metastasis, and to the selection, expansion, and chemoresistance of breast cancer stem cells. In trying to unravel these mysteries, we combine contemporary techniques in molecular and cellular biology, in biochemistry, and in genomic- and proteomic-based differential gene expression analyses. We also translate our in vitro analyses into animal models capable of interrogating the function of TGF-β in (i) promoting the growth, invasion, and metastasis of mammary tumors produced in mice, and (ii) visualizing the activation of oncogenic TGF-β effectors in developing and progressing mammary tumors in mice.
Major ongoing research efforts are directed at understanding (i) the role of integrins, focal adhesion complexes, and protein tyrosine kinases in regulating the oncogenic activities of TGF-β; (ii) the function of NF-κB and Cox-2 in mediating breast cancer cell resistance to TGF-β; (iii) the mechanisms whereby c-Abl phenotypically and morphologically normalizes the malignant behaviors of metastatic breast cancer cells; and (iv) the mechanisms whereby altered tumor microenvironments and mechanotransduction impact breast cancer cell response to TGF-β, particularly its regulation of microRNAs. A final focus of the lab seeks to translate and develop these findings into novel cancer chemotherapeutics capable of selectively targeting the oncogenic activities of TGF-β; and, consequently, of "normalizing" malignant tissues in such a way that cancer itself can be converted from an acute, symptomatic, and life-threatening disease to one that is chronic, asymptomatic, and manageable through the normal lifespan of affected individuals.
Galliher-Beckley, A.J. and Schiemann, W.P. (2008) Grb2 binding to Tyr284 in TβR-II is essential for mammary tumor growth and metastasis stimulated by TGF-β. Carcinogenesis 29: 244-251.
Neil, J.R. and Schiemann, W.P. (2008) Altered TAB1:IKK interaction promotes TGF-β-mediated NF-κB activation during breast cancer progression. Cancer Res 68: 1462-1470.
Albig, A.R., Roy, T.G., Becenti, D.J. and Schiemann, W.P. (2008) MAGP-2 promotes angiogenic cell sprouting by blocking Notch signaling in endothelial cells. Microvasc Res 76: 7-14.
Xiao, Y.Q., Freire-de-Lima, C.G., Schiemann, W.P., Bratton, D.L., Vandivier, R.W. and Henson, P.M. (2008) Transcriptional and translational regulation of TGF-β production in response to apoptotic cells. J Immunol 181: 3575-3585.
Lee, Y-H., Albig, A.R., Neil, J.R., Regner, M. Schiemann, B.J. and Schiemann, W.P. (2008) Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-β in mammary epithelial cells via a MMP-dependent mechanism. Carcinogenesis 29: 2243-2251.
Neil, J.R., Johnson, K.M., Nemenoff, R.A. and Schiemann, W.P. (2008) COX-2 inactivates Smad signaling and enhances EMT stimulated by TGF-β through a PGE2-dependent mechanism. Carcinogenesis 29: 2227-2235.
Tian, M. and Schiemann, W.P. (2009) Preclinical efficacy of Cystatin C to target the oncogenic activity of TGF-β in breast cancer. Transl Oncol 2: 174-183.
Neil, J.R., Tian, M. and Schiemann, W.P. (2009) xIAP and its E3 ligase activity promote TGF-Β-mediated NF-κB activation during breast cancer progression. J Biol Chem 284: 21209-21217.
Micalizzi, D.S., Christensen, K.K., Jedlicka, P., Coletta, R.D., Baron, A.E., Harrell, J.C., Horwitz, K.B., Billheimer, D., Heichman, K.A., Welm, A.L., Schiemann, W.P. and Ford, H.L. (2009) The Six1 homeoprotein induces epithelial-mesenchymal-transition and breast cancer metastasis via increasing TGF-β signaling. J Clin Invest 119: 2678-2690.
Allington, T.M., Galliher-Beckley, A.J. and Schiemann, W.P. (2009) Activated Abl kinase inhibits oncogenic TGF-β signaling and tumorigenesis in breast cancer cells. FASEB J 23: 4231-4243.
Tian, M. and Schiemann, W.P. (2009) The TGF-β paradox in human cancer: An update. Future Oncol 5: 259-271.
Wendt, M.K. and Schiemann, W.P. (2009) Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-β signaling and metastasis. Breast Cancer Res 11: R68.
Keshamouni, V.G. and Schiemann, W.P. (2009) EMT in Tumor Metastasis: A Method to the Madness. Future Oncol 5: 1109-1111.
Wendt, M.K., Allington, T.M. and Schiemann, W.P. (2009) Mechanisms of epithelial-mesenchymal transition by TGF-β in normal and malignant cells. Future Oncol 5: 1145-1168.
Wendt, M.K., Smith, J.A. and Schiemann, W.P. (2009) p130Cas is required for mammary tumor growth and TGF-β-mediated metastasis through regulation of Smad2/3 activity. J Biol Chem 284: 34145-34156.
Tian, M. and Schiemann, W.P. (2010) PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-β signaling during mammary tumorigenesis. FASEB J 24: 1105-1116.
Peng, A., Lewellyn, A., Schiemann, W.P. and Maller, J.L. (2010) Repo-man controls a protein phosphatase 1-dependet threshold for DNA damage checkpoint activation. Curr Biol 20: 387-396.
Taylor, M.A., Parvani, J.G. and Schiemann, W.P. (2010) The pathophysiology of EMT stimulated by TGF-β. J Mammary Gland Biol Neoplasia 15: in press.
Allington, T.M. and Schiemann, W.P. (2010) The Cain and Abl of epithelial-mesenchymal transition and TGF-β in mammary epithelial cells. Cells Tissues Organs in press.