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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.
Selected Publications
Lewis MT (2000) Homeobox genes in mammary gland development and neoplasia. Breast Cancer Research 2:158-169.
Lewis MT (2001) Hedgehog signaling in mouse mammary gland development and neoplasia. Journal of Mammary Gland Biology and Neoplasia 6:53-66.
Lewis MT, Ross S, Strickland PA, Sugnet CW, Jimenez E, Hui C, Daniel CW (2001) The Gli2 transcription factor is required for normal mouse mammary gland development.
Developmental Biology 238:133-144.
Salomon DS, Lewis MT (2004) Embryogenesis and oncogenesis: Dr Jekyll and Mr Hyde. Journal of Mammary Gland Biology and Neoplasia 9:105-107.
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 U.S.A. 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.
Kim HJ, Litzenburger BC, Cui X, Delgado DA, Grabiner BC, Lin X, Lewis MT, Gottardis MM, Wong TW, Attar RM, Carboni JM, Lee AV (2007) Constitutively active type I
insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition
mediated by NF-κβ and snail. Molecular and Cellular Biology 27:3165-3175.
Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC (2008) Intrinsic resistance of
tumorigenic breast cancer cells to chemotherapy. Journal of the National Cancer Institute 100:672-679.
Contact Information
- Michael T. Lewis, Ph.D.
- Lester and Sue Smith Breast Center
- Baylor College of Medicine
- One Baylor Plaza
- Houston, Texas 77030, U.S.A.
- Lab website
- Tel: (713) 798-3296
- Fax: (713) 798-1659
- E-mail: mtlewis@bcm.edu
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