In our first grant, we provided evidence that ectopic Wnt signaling induces breast tumors via a stemprogenitor cell precursor. This is likely to be a forerunner of a larger class of tumors with a different etiology. Thus, experience gained from treating human patients with tumors arising in the stem cell compartment (like chronic myelogenous leukemia) has shown that effective therapeutic strategies require the underlying stem cell biology to be analyzed and understood. We propose that by studying Sdc1-/- mice, we will be able to characterize features that make a stem-progenitor compartment vulnerable to transformation. Thus we have found that these mice are resistant to tumor development in response to oncogenes that target stemprogenitor cells (in mammary gland in response to Wnt effectors) and in response to carcinogens (in all major classes of tumors). We will focus particularly on analyzing carcinogen-induced tumors, since these (like Wnt-induced tumors) have the hallmarks associated with a stem cell precursor, and are likely to have direct relevance to human breast cancer. Although Sdc1-/- mice have only marginally depleted stemprogenitor number in mammary arid hematopoietic lineages, they have low stem cell activity. Here, we test the hypothesis that Sdc1-/- somatic stem cell lineages are underactive, and that this confers their resistance to carcinogens. We will test the nature of the defect in Sdc1-/- mammary stem cell activity, the reaction of stem-progenitor cells to carcinogen administration, the origins of carcinogen-induced tumors, and the molecular basis of the defect induced by the absence of Sdc1. This defect may apply not only to mammary and hematopoietic lineages but to many others, including hematopoietic stem cells and solid organs such as lung and liver. By understanding the defects in these mice we aim to find out when somatic stem cell compartments are prone to transformation, and what factors regulate this process.

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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