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Research Interests: Mammary stem cells; Mouse mammary tumor models; Wnt signaling; Syndecan-1

Research Description: We are studying aspects of mammary gland biology and neoplasia using transgenic mouse models. Particularly, we have found that Wnt signaling dysregulates mammary stem cells, and that this precedes the formation of differentiated, bilineal tumors.  Wnt signaling is highly oncogenic to mammalian epithelia, and indeed comprises one of the main sources of human tumor initiation identified to date.  Our hypothesis is that the transforming potential of Wnt signaling is unique to stem/progenitor cells.  Our work aims at elucidating how and when adult somatic stem cells can be recruited as tumor precursor cells.  Current projects include:

1. The discovery of the molecular and cellular mechanism that underlies the tumor resistance phenotype illustrated by mice with a mutation in the heparan sulfate proteoglycan, syndecan-1 (Sdc1) (McDermott et al 2006). 
   
2. Modeling of stem cell-based breast cancer
   
3. The activation of stromal cells and their recruitment to tumor development during Wnt-induced tumorigenesis
   
4. The analysis of adult stem cell responses during tumor initiation
   
5. Determination of how Wnt signaling supports normal mammary stem cell function
   
6. An investigation of cell-cell interactions in mammary gland, using microchannel cultures to identify endogenous growth promoting and inhibiting substances secreted by minor sub-populations

CMA is the recipient of an Era of Hope Scholar Award 2006 – 2011 (Dept. of Defense)

Selected recent publications

Badders, N. M., Goel, S., Clark, R. J., Klos, K. S., Kim, S., Bafico, A., Lindvall, C., Williams, B. O., and Alexander, C. M.  The Wnt Receptor, Lrp5, Is Expressed by Mouse Mammary Stem Cells and Is Required to Maintain the Basal Lineage.  PLoS ONE, 4(8):e6594, 2009.

Kim, Y. C., Clark, R. J., Pelegri, F., and Alexander, C. M.  Wnt4 Is Not Sufficient to Induce Lobuloalveolar Mammary Development.  BMC Dev. Biol. 9:55, 2009.

Mastroianni, M., Kim, S., Kim, Y. C., Esch, A., Wagner, C., and Alexander, C. M.  Wnt Signaling Can Substitute for Estrogen to Induce Division of ERα-Positive Cells in a Mouse Mammary Tumor Model.  Cancer Lett., in press, 2009 [Epub ahead of print Aug 7 2009].

Alexander, C. M.  Base Behavior behind Budding Breasts:  Integrins and Mammary Stem Cell Activity.  Cell Stem Cell, 3:  5-6, 2008.

Badders, N. M., Yu, H., Alexander, C. M., and Beebe, D. J.  Quantification of Small Cell Numbers with a Microchannel Device.  BioTechniques, 45:  321-325, 2008.

Kim, Y. C., Clark, R. J., Ranheim, E. A., and Alexander, C. M.  Wnt1 Expression Induces Short-Range and Long-Range Cell Recruitments That Modify Mammary Tumor Development and Are Not Induced by a Cell-Autonomous β-Catenin Effector.  Cancer Res., 68:  10145-10153, 2008.

Chen, S., Zheng, T., Shortreed, M. R., Alexander, C., and Smith, L. M.  Analysis of Cell Surface Carbohydrate Expression Patterns in Normal and Tumorigenic Human Breast Cell Lines Using Lectin Arrays.  Anal. Chem., 79:  5698-5702, 2007.

McDermott, S. P., Ranheim, E. A., Leatherberry, V. S., Khwaja, S. S., Klos, K. S., and Alexander, C. M.  Juvenile Syndecan-1 Null Mice Are Protected from Carcinogen-induced Tumor Development.  Oncogene, 26: 1407-1416, 2007.

Paguirigan, A., Beebe, D. J., and Alexander, C. M.  Simulating Mouse Mammary Gland Development:  Cell Ageing and Its Relation to Stem and Progenitor Activity.  Cell Prolif., 40:  106-124, 2007.

Slavik, M. A., Allen-Hoffmann, B. L., Liu, B. Y., and Alexander, C. M.  Wnt Signaling Induces Differentiation of Progenitor Cells in Organotypic Keratinocyte Cultures.  BMC Dev. Biol., 7:9, 2007.

Yu, H., Alexander, C. M., and Beebe, D. J.  A Plate Reader-compatible Microchannel Array for Cell Biology Assays.  Lab Chip, 7:  388-391, 2007.

Yu, H., Alexander, C. M., and Beebe, D. J.  Understanding Microchannel Culture:  Parameters Involved in Soluble Factor Signaling.  Lab Chip, 7:  726-730, 2007.

Zheng, T., Yu, H., Alexander, C. M., Beebe, D. J., and Smith, L. M.  Lectin-modified Microchannels for Mammalian Cell Capture and Purification.  Biomed. Microdevices, 9:  611-617, 2007.

Lindvall, C., Evans, N. C., Zylstra, C. R., Li, Y., Alexander, C. M., and Williams, B. O.  The Wnt Signaling Receptor Lrp5 Is Required for Mammary Ductal Stem Cell Activity and Wnt1-induced Tumorigenesis.  J. Biol. Chem., 281:  35081-35087, 2006.

Paguirigan, A., Beebe, D. J., Liu, B., and Alexander, C.  Mammary Stem and Progenitor Cells:  Tumour Precursors?  Eur. J. Cancer, 42:  1225-1236, 2006.

Liu, B. Y., McDermott, S. P., Khwaja, S. S., and Alexander, C. M. The Transforming Activity of Wnt Effectors Correlates with Their Ability to Induce the Accumulation of Mammary Progenitor Cells. Proc. Natl. Acad. Sci. USA, 101: 4158-4163, 2004.

Maeda, T., Alexander C. M., and Friedl, A. Induction of Syndecan-1 Expression in Stromal Fibroblasts Promotes Proliferation of Human Breast Cancer Cells. Cancer Res., 64: 612-621, 2004.

Liu, B. Y., Kim, Y. C., Leatherberry, V., Cowin, P., and Alexander, C. M. Mammary Gland Development Requires Syndecan-1 to Create a b-Catenin/TCF-Responsive Mammary Epithelial Subpopulation. Oncogene, 22: 9243-9253, 2003.

Wiseman, B. S., Sternlicht, M. D., Lund, L. R., Alexander, C. M., Mott, J., Bissell, M. J., Soloway, P., Itohara, S., and Werb, Z. Site-Specific Inductive and Inhibitory Activities of MMP-2 and MMP-3 Orchestrate Mammary Gland Branching Morphogenesis. J. Cell Biol., 162: 1123-1133, 2003.

Alexander, C.M., Selvarajan, S., Mudgett, J., and Werb, Z. Stromelysin-1 Regulates Adipogenesis during Mammary Gland Involution. J. Cell. Biol., 152: 693-703, 2001.

Klinowska, T.C., Alexander, C.M., Georges-Labouesse, E., Van der Neut, R., Kreidberg, J.A., Jones, C.J., Sonnenberg, A., and Streuli, C.H. Epithelial Development and Differentiation in the Mammary Gland is not Dependent on Alpha 3 or Alpha 6 Integrin Subunits. Dev. Biol., 233: 449-467, 2001.

Alexander, C.M., Mudgett, J.S., Hansell, E.J., Berger, J., and Werb, Z. Matrix Metalloproteinase Function during Mammary Gland Involution. In: S. Hawkes and D. Edwards, and R. Khokha (Eds.), Tissue Inhibitors of Metalloproteinases in Development and Disease. Amsterdam: Harwood Academic, 2000.

Alexander, C.M., Reichsman, F., Hinkes, M.T., Lincecum, J., Becker, K.A., Cumberledge, S., and Bernfield, M.  Syndecan-1 Is Required for Wnt-1-induced Mammary Tumorigenesis in Mice.  Nature Genet., 25: 329-332, 2000.

Alexander, C. M. Book Review: Cells: A Lab Manual. D. L. Spector, R. D. Goldman, and L. A. Leinwand (Eds). Trends Genet., 14: 294, 1998.

Alexander, C.M., Hansell, E.J., Behrendtsen, O., Flannery, M.L., Kishnani, N.S., Hawkes, S.P., and Werb, Z. Expression and Function of Matrix Metalloproteinases and Their Inhibitors at the Maternal-Embryonic Boundary during Mouse Embryo Implantation. Development, 122: 1723-1736, 1996.

Alexander, C.M., Howard, E.W., Bissell, M.J., and Werb, Z. Rescue of Mammary Epithelial Cell Apoptosis and Entactin Degradation by a TIMP-1 Transgene. J. Cell Biol., 135: 1669-1677, 1996.

Soloway, P.D., Alexander, C.M., Werb, Z., and Jaenisch, R. Targeted Mutagenesis of TIMP-1 Reveals that Lung Tumor Invasion is Influenced by TIMP-1 Genotype of the Tumor but not by that of the Host. Oncogene, 13: 2307-2314, 1996.

Werb, Z., Sympson, C. J., Alexander, C. M., Thomassett, N., Lund, L. R., MacAuley, A., Ashkenas, J., and Bissell, M. J. Extracellular Matrix Remodeling and the Regulation of Epithelial-Stromal Interactions during Differentiation and Involution. Kidney Int., 49: 68-74, 1996.