Caroline Alexander, PhD

Portrait of Caroline Alexander, PhD
Associate Professor
Oncology
Address: 
819A McArdle
1400 University Avenue
Madison, WI 53706
Telephone: 
(608) 265-5182
Focus Groups: 
Cancer Biology
Signal Transduction
Education: 
PhD, Cell Biology and Biochemistry, University of Kent, England
Postdoctoral research: Imperial Cancer Research Fund, London and UC-San Francisco
Research Summary: 
Mammary stem cells; Mouse mammary tumor models; Wnt signaling; Syndecan-1
Research Detail: 

We are studying aspects of mammary gland biology and neoplasia using transgenic mouse models. Our lab has two main foci. The first focus is to determine the molecular and cellular basis for Wnt-induced tumors. Particularly, we have found that Wnt signaling dysregulates mammary stem cells, and that this precedes the formation of tumors with mixtures of cells (that resemble human basaloid breast cancers). 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 Wnt signaling induces a plastic state of mammary cell differentiation that confers stem cell properties. Our analysis of the Wnt receptor, Lrp5, has shown that only specific Wnt signals work to induce and maintain adult mammary somatic stem cells. Our second focus is the elucidation of the mechanism for the generalized tumor resistance phenotype shown by mice with a mutation in the heparan sulfate proteoglycan, syndecan-1. This turns out to be a metabolic syndrome, and links syndecan-1 to lipid uptake, and lipid uptake to tumor susceptibility.

 

  • Current projects include:
  • Investigation of the molecular and cellular mechanism underlying the tumor resistance phenotype of mice with a mutation in the heparan sulfate proteoglycan, syndecan-1 (Sdc1) (McDermott et al., 2006; Suh, Kasza et al., in preparation).
  • Search for tumor drivers in a novel model of basaloid breast cancer (Kim et al., 2010; Kim et al., 2011).
  • Dissection of the Wnt signaling complexes that maintain mouse mammary stem cells (Badders et al., 2009; Goel et al., 2012).
  • Interrogation of the role of CRD-BP, an RNA binding protein, in the fate determination and tumorigenesis of mammary epithelia (collaboration with V. Spiegelman, Dermatology).
Selected Publications: 
K.S. Klos, S. Kim and C.M. Alexander. Genotoxic Exposure During Juvenile Growth of Mammary Gland Depletes Stem Cell Activity and Inhibits Wnt Signaling. PLoS ONE, 7(11): e49902, 2012.
Alexander, C. M., Goel, S., Fakhraldeen, S. A., and Kim, S. Wnt Signaling in Mammary Glands: Plastic Cell Fates and Combinatorial Signaling. Cold Spring Harbor Perspect. Biol., in press, 2012 [Epub ahead of print, Jun 1 2012].
Goel, S., Chin, E. N., Fakhraldeen, S. A., Berry, S. M., Beebe, D. J., and Alexander, C. M. Both LRP5 and LRP6 Receptors Are Required to Respond to Physiological Wnt Ligands in Mammary Epithelial Cells and Fibroblasts. J. Biol. Chem., 287: 16454-16466, 2012.
Gunsalus, K. T. W., Wagoner, M. P., Meyer, K., Potter, W. B., Schoenike, B., Kim, S., Alexander, C. M., Friedl, A., and Roopra, A. Induction of the RNA Regulator LIN28A Is Required for the Growth and Pathogenesis of RESTless Breast Tumors. Cancer Res., 72: 3207-3216, 2012.
Kim, S., Roopra, A., and Alexander, C. M. A Phenotypic Mouse Model of Basaloid Breast Tumors. PLoS ONE, 7(2):e30979, 2012.
Thliveris, A. T., Clipson, L., Sommer, L. L., Schoenike, B. A., Hasenstein, J. R., Schlamp, C. L., Alexander, C. M., Newton, M. A., Dove, W. F., and Amos-Landgraf, J. M. Regulated Expression of Chromobox Homolog 5 Revealed in Tumors of ApcMin/+ ROSA11 Gene Trap Mice. G3 (Bethesda), 2: 569-578, 2012.
Kim, S., Goel, S., and Alexander C. M. Differentiation Generates Paracrine Cell Pairs That Maintain Basaloid Mouse Mammary Tumors: Proof of Concept. PLoS One, 6(4):e19310, 2011.
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., 289: 23-31, 2010.
Alexander, C. M., Puchalski, J., Klos, K. S., Badders, N., Ailles, L., Kim, C. F., Dirks, P., and Smalley, M. J. Separating Stem Cells by Flow Cytometry: Reducing Variability for Solid Tissues. Cell Stem Cell, 5: 579-583, 2009
Badders, N.M., Goel, S. Clark, R.J., 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.