Michael T. Lewis, Ph.D.
Department Molecular and Cellular Biology (Lester and Sue Smith Breast Center)
Ph.D.: University of California, Santa Cruz
Postdoctoral training: University of California, Santa Cruz
University of Colorado Health Sciences Center, Denver
Mammary Gland Development and 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.
Diagram of the growing terminal end bud (TEB) of a developing mammary duct. Major cell types and structures required for mammary gland development are shown.
Baylor College of Medicine
One Baylor Plaza, Room N1210
Houston, TX 77030
- Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu M, Hilsenbeck SG, Pavlick A, Chamness G, Wong H, Rosen J and Chang JC. (2008). Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst (In press).
- Zhang X, Harrington N, Moraes R, Wu M, Hilsenbeck S and Lewis MT. (2008). Cyclopamine inhibition of human breast cancer cell growth independent of Smoothened (Smo). Breast Cancer Research and Treatment (In press).
- Moraes RC, Zhang X, Harrington N, Fung JY, Wu MF, Hilsenbeck SG, Allred DC and Lewis MT. (2007). Constitutive activation of Smoothened (Smo) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation, and ductal dysplasia. Development 134:1231-42.
- Kim HJ, Litzenburger BC, Cui X, Delgado DA, Grabiner BC, Lin X, Lewis MT, Gottardis MM, Wong TW, Attar RM, Carboni J and Lee AV. (2007). Constitutively active IGF-IR causes transformation and xenograft growth of immortalized mammary epithelial cells, and is accompanied by an epithelial to mesenchymal transition mediated by NF-kappaβ and Snail. Mol Cell Biol 27:3165-75.
- Du Z, Podsypanina K, Huang S, McGrath A, Toneff MJ, Bogoslovskaia E, Zhang X, Moraes RC, Fluck M, Allred DC, Lewis MT, Varmus HE and Li Y. (2006). Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models. Proc Natl Acad Sci 103:17396-401.
- Lewis MT and Visbal AP. (2006). The hedgehog signaling network, mammary stem cells, and breast cancer: connections and controversies. Ernst Schering Fdn Symposium Proceedings 5:181-217.
- 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 and O’Connell P. (2005). Patterns of resistance and incomplete response to docetaxel (Taxotere) by gene expression profiling in breast cancer patients. Journal of Clinical Oncology 23(6):1169-77.
- Lewis MT and Veltmaat JM. (2004). Next stop, the twilight zone: hedgehog network regulation of mammary gland development. J Mammary Gland Biol Neoplasia 9:165-181.
- Lewis MT, Ross S, Strickland PA, Sugnet C, Jimenez E, Hui C-c and Daniel CW. (2001). The Gli2 transcription factor is required for normal mouse mammary gland development. Dev Biol 238:133-144.
- Lewis MT, Ross S, Strickland PA, Sugnet C, Jimenez E, Scott MP and Daniel CW. (1999). Defects in mouse mammary gland development caused by conditional haploinsufficiency of Patched-1 (Ptc1). Development 126:5181-5193.