By using mouse models, the molecules that affect the development of mammary tumors can be identified and manipulated. Various stages in the pathway to neoplasia can be characterized, including the initial growth dysregulation that serves as a precursor for tumor cells in both mouse and man. Heparan sulfate proteoglycans bind many extracellular molecules, and affect the function of at least some of them, including FGF. The cell surface heparan sulfate proteoglycan syndecan-1 (Sdc1) has been shown to collaborate with the oncogene Wnt-1 to induce hyperplasia and subsequently tumors in mouse mammary glands (Alexander et al, 2000. Nature Genetics 25, p329). Given the widespread dysregulation of Writ signaling pathways implicated in human carcinomas of many different origins, this is an important genetic interaction to characterize at the molecular level. Therefore, we aim to determine how Sdc1 interacts with the Wnt signaling pathway, using transgenic mice and genetically manipulated primary mammary epithelial cells. Mammary glands will be reconstituted in vivo by inoculating transgenic cells into host fat pads, and the activity of the Wnt signaling pathway assessed by measuring epithelial hyperplasia. This novel method conveniently tests the interaction of multiple gene products in vivo. Thus, the growth and dysregulation of Sdc1+/+ and -/- mammary epithelial cells, expressing various Sdc1 and Wnt signaling mutants, will be assessed both in vitro and in vivo. Soluble Sdc1 promotes Wnt signaling in a Drosophila culture model, and may function as a collaborator to augment signaling from the cell surface receptor complex. We will test this hypothesis by examining the epistatic interaction of Sdc1 with the primary Wnt signaling transducer, beta-catenin, and by testing for a direct interaction of Sdc1 with Wnt ligands. Sdc1- /- mice will be infected with mouse mammary tumor virus (MMTV), a mutagen that can be used to identify oncogenic loci, in order to evaluate the relative oncogenicity of specific loci and to broaden the test of tumor susceptibility in this background. In summary, this proposal aims to establish the molecular mechanism underlying the collaboration between Sdc1 and the Wnt signaling pathway that has been demonstrated in mice and may be important to man.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Sathyamoorthy, Neeraja
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University of Wisconsin Madison
Internal Medicine/Medicine
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United States
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Alexander, Caroline M; Kasza, Ildiko; Yen, C-L Eric et al. (2015) Dermal white adipose tissue: a new component of the thermogenic response. J Lipid Res 56:2061-9
Kasza, Ildiko; Suh, Yewseok; Wollny, Damian et al. (2014) Syndecan-1 is required to maintain intradermal fat and prevent cold stress. PLoS Genet 10:e1004514
Alexander, Caroline M; Joshi, Purna A; Khokha, Rama (2014) Fully interlocking: a story of teamwork among breast epithelial cells. Dev Cell 28:114-5
Kim, Soyoung; Alexander, Caroline M (2014) Tumorsphere assay provides more accurate prediction of in vivo responses to chemotherapeutics. Biotechnol Lett 36:481-8
Mastroianni, Melissa; Kim, Soyoung; Kim, Young Chul et al. (2010) Wnt signaling can substitute for estrogen to induce division of ERalpha-positive cells in a mouse mammary tumor model. Cancer Lett 289:23-31
Kim, Young Chul; Clark, Rod J; Pelegri, Francisco et al. (2009) Wnt4 is not sufficient to induce lobuloalveolar mammary development. BMC Dev Biol 9:55
Alexander, Caroline M; Puchalski, Joel; Klos, Kristine S et al. (2009) Separating stem cells by flow cytometry: reducing variability for solid tissues. Cell Stem Cell 5:579-83
Badders, Nisha M; Goel, Shruti; Clark, Rod J et al. (2009) The Wnt receptor, Lrp5, is expressed by mouse mammary stem cells and is required to maintain the basal lineage. PLoS One 4:e6594
Kim, Young Chul; Clark, Rod J; Ranheim, Erik A et al. (2008) Wnt1 expression induces short-range and long-range cell recruitments that modify mammary tumor development and are not induced by a cell-autonomous beta-catenin effector. Cancer Res 68:10145-53
McDermott, S P; Ranheim, E A; Leatherberry, V S et al. (2007) Juvenile syndecan-1 null mice are protected from carcinogen-induced tumor development. Oncogene 26:1407-16

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