Associate Professor, Baylor College of Medicine
B.S., College of William and Mary, VA, 1986
Ph.D., University of California, Santa Cruz, 1995
Postdoc, University of California, Santa Cruz, 1995-98
Postdoc, University of Colorado, Denver, 1999
Genetic regulation of mammary gland development and early-stage breast cancer
Our laboratory studies normal mammary gland development and breast cancer primarily using mouse genetic models and human xenografts. Our current focus is on the role of hedgehog signaling and homeobox genes in normal development, and on the characterization of breast cancer stem cells, particularly with respect to treatment resistance.
Early detection of breast cancer is widely recognized as a key to effective treatment, yet little is known about the progression from a normal to a cancerous state. In fact, one of the limiting factors in understanding breast cancer is our lack of knowledge about how the breast develops normally. Without a more complete understanding of the normal mammary gland, particularly normal stem and progenitor cells, early detection of breast cancer will continue to be difficult, and discovery of new therapeutic agents will be hindered significantly.
In the normal breast, growth and maintenance of breast tissue depends on communication between cells in the ducts (the epithelium) and in the surrounding “stroma”. Disruption of these cell-cell interactions is a hallmark of the transition from a normal to a neoplastic state, and contributes to breast cancer progression. One of the primary signaling networks regulating these interactions is the “hedgehog” network. Of particular interest to us is the fact that homeobox genes, a large group of master developmental regulators, frequently mediate the downstream effects of active hedgehog signaling. We are exploring the functional relationships between hedgehog network and homeobox genes in our work.
Our laboratory also studies the role of “cancer stem cells” in tumor growth and in treatment resistance. Our data suggest that these cells may, by their nature, be intrinsically resistant to traditional breast cancer therapeutics, including chemotherapy. Our goal is to understand these cells in detail, and to discover novel therapeutics that can eliminate these cells from breast cancer in patients.
Lewis MT, Veltmaat JM (2004) Next stop, the twilight zone: hedgehog network regulation of mammary gland development. Journal of Mammary Gland Biology and Neoplasia 9:165-181.
Chang JC, Wooten EC, Tsimelzon A, Hilsenbeck SG, Gutierrez MC, Tham YL, Kalidas M, Elledge R, Mohsin S, Osborne CK, Chamness GC, Allred DC, Lewis MT, Wong H, O’Connell P (2005) Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients. Journal of Clinical Oncology 23:1169-1177.
Du Z, Podsypanina K, Huang S, McGrath A, Toneff MJ, Bogoslovskaia E, Zhang X, Moraes RC, Fluck M, Allred DC, Lewis MT, Varmus HE, Li Y (2006) Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models. Proceedings of the National Academy of Sciences USA 103:17396-17401.
Moraes RC, Zhang X, Harrington N, Fung JY, Wu MF, Hilsenbeck SG, Allred DC, Lewis MT (2007) Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia. Development 134:1231-1242.
Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, Rimm DL, Wong H, Rodriguez A, Herschkowitz JI, Fan C, Zhang X, He X, Pavlick A, Gutierrez MC, Renshaw L, Larionov AA, Faratian D, Hilsenbeck SG, Perou CM, Lewis MT, Rosen JM, Chang JC (2009) Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proceedings of the National Academy of Sciences USA 106:13820-13825.
Herynk MH, Lewis MT, Hopp TA, Medina D, Corona-Rodriguez A, Cui Y, Beyer AR, Fuqua SA (2009) Accelerated mammary maturation and differentiation, and delayed MMTVneu-induced tumorigenesis of K303R mutant ERalpha transgenic mice. Oncogene 28:3177-3187.
Landua JD, Visbal AP, Lewis MT (2009) Methods for preparing fluorescent and neutral red-stained whole mounts of mouse mammary glands. Journal of Mammary Gland Biology and Neoplasia 14:411-415.
Moraes RC, Chang H, Harrington N, Landua JD, Prigge JT, Lane TF, Wainwright BJ, Hamel PA, Lewis MT (2009) Ptch1 is required locally for mammary gland morphogenesis and systemically for ductal elongation. Development 136:1423-1432.
Zhang X, Harrington N, Moraes RC, Wu MF, Hilsenbeck SG, Lewis MT (2009) Cyclopamine inhibition of human breast cancer cell growth independent of Smoothened (Smo). Breast Cancer Research and Treatment 115:505-521.
Visbal AP, Lewis MT (2010) Hedgehog signaling in the normal and neoplastic mammary gland. Current Drug Targets 11:1103-1111.
Visbal AP, LaMarca HL, Villanueva H, Toneff MJ, Li Y, Rosen JM, Lewis MT (2011) Altered differentiation and paracrine stimulation of mammary epithelial cell proliferation by conditionally activated Smoothened. Developmental Biology 352:116-127.
Michael T. Lewis, Ph.D.
Lester and Sue Smith Breast Center
Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030, U.S.A.
Tel: (713) 798-3296
Fax: (713) 798-1659