There are a group of breast tumors that have a significantly worse prognosis than the others, the so-called triple negative tumors (ER-ve, PR-ve, HER2-). One reason for their poor prognosis is a lack of targeted therapies (they are non-responsive to tamoxifen or herceptin). In this application, it is postulated that carcinogen-induced breast tumors in mice are a good model of triple negative breast cancer. By transcriptional profiling, they cluster in a mouse subgroup (including tumors from BRCA1, p53 and Wnt transgenic mice) that resembles the profile of basaloid, triple negative group from women. They have markers of bilineal differentiation, which implies the presence of a cancer stem cell. In the literature, there is some data to suggest that other types of cancer stem cells are relatively resistant to the standard chemo- and radiotherapeutic strategies, and that this could be the reason for tumor recurrence or non- responsiveness. This application seeks to resolve a classic dilemma in this field, which is whether the tumor precursor cells are drawn from normal stem cells in the breast. If the process of recruitment is better understood, it may be possible to understand not only how to prevent precursor transformation, but also whether the cancer stem cells share more properties with normal stem cells (or have acquired just one specific function that confers immortal growth potential). A specific mouse strain with a mutant allele of a heparan sulfate proteoglycan, syndecan1 (Sdc1), is dramatically resistant to carcinogen- and oncogene- induced tumors and is suspected to have a key deficiency in the pathogenic activation of stem/progenitor cells. This mouse strain therefore represents a tool that can help to pinpoint a highly susceptible stage of cancer initiation. In this application, the Aims include the elucidation of the origin of carcinogen-induced tumors (using a newly developed mouse strain based on the discovery of LRP5 as a mammary stem cell biomarker), the discovery of the cellular mechanism of tumor protection in Sdc1-/- mice, a description of the specific response of stem, progenitor and differentiated cell fractions to genotoxic carcinogen administration, and the elucidation of the molecular pathways that underlie their resistance to tumor development. The initiating events that start this tumor process are currently not at all understood, and the analysis of this mouse strain represents a unique opportunity for discovery.
A specific strain of mouse (carrying a mutation in the syndecan-1 gene, a cell surface heparan sulfate proteoglycan) is dramatically resistant to tumors that develop after treatment with carcinogens. There is evidence to suggest that the precursor cells for these tumors originate in the normal stem cell compartment, and that they are mutated to become "cancer stem cells". Analysis of the response of breast tissue from these mice during carcinogen administration can pinpoint the factors that regulate the recruitment of mammary stem cells to tumors, and advise on how to reduce tumor load after carcinogen exposure.
|Kim, Soyoung; Alexander, Caroline M (2014) Tumorsphere assay provides more accurate prediction of in vivo responses to chemotherapeutics. Biotechnol Lett 36:481-8|
|Alexander, Caroline M; Joshi, Purna A; Khokha, Rama (2014) Fully interlocking: a story of teamwork among breast epithelial cells. Dev Cell 28:114-5|
|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|
|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|
|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|
|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|
|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|
|Slavik, Marni A; Allen-Hoffmann, B Lynn; Liu, Bob Y et al. (2007) Wnt signaling induces differentiation of progenitor cells in organotypic keratinocyte cultures. BMC Dev Biol 7:9|
|Paguirigan, A; Beebe, D J; Alexander, C M (2007) Simulating mouse mammary gland development: cell ageing and its relation to stem and progenitor activity. Cell Prolif 40:106-24|
Showing the most recent 10 out of 12 publications