The objective of this proposal is to understand the role of mammary adipocytes and adipocyte-secreted factors (such as, Type-VI collagen): i) in the growth/survival of mammary epithelial cells; and ii) in the pathogenesis of breast cancer. Mammary epithelial cells/ducts are embedded in a matrix that consists predominantly of adipocytes. However, it remains unknown what adipocyte-secreted factors are required for the survival of mammary epithelia. Similarly, these unknown adipocyte-specific factors may contribute to the pathogenesis of human breast cancers. To test this hypothesis, we will use a variety of novel in vivo approaches, such as """"""""reconstituted mammary fat pads (RFPs)"""""""" employing the transfectable 3T3-L1 model adipocyte cell line, and Type-VI collagen (-/-) null mice. The three specific aims of the project are: 1) To identify paracrine interactions between mammary epithelia and their surrounding adipocytes. We will establish co-culture and conditioned media systems using 3T3-L1 adipocytes and the human breast cancer epithelial cell line, MCF-7. We will use microarray analysis to define adipocyte-induced transcriptional changes in MCF-7 and thereby identify genes that mediate the growth and survival of MCF-7 cells. To functionally examine the role of specific factors, we will generate """"""""reconstituted fat pads (RFPs)"""""""" using stably-transfected 3T3-L1 adipocytes over-expressing a given gene product. These RFPs will be co-implanted with MCF-7 cells into nude mice to assess their contribution to tumorigenicity in vivo; 2) To determine the role of Type-VI collagen in mammary tumorigenesis. Our preliminary data demonstrate that Type-VI collagen is an abundant extracellular matrix component of mammary tissue that is secreted by adipocytes and that is up-regulated during mammary tumor progression. We will cross Type-VI collagen null mice with an established mouse model of mammary tumorigenesis, MMTV-ErbB2/Neu. We predict that loss of Type-VI collagen expression will block or diminish the development of mammary tumors; and 3) To determine if selective ablation of mammary adipocytes in the adult mouse prevents or diminishes mammary tumor development. For this purpose, we have developed a novel transgenic inducible system that allows the selective apoptotic ablation of mammary adipocytes, in a temporally controlled fashion that will be crossed to MMTV-PyMT mice. In a complementary approach, we will induce the selective-ablation of mammary epithelial cells. We have placed a ligand-activatable transgenic cassette containing pro-caspase-8 under the control of the aP2-promoter (for expression in adipocytes) and the MMTV-promoter (for expression in mammary epithelia). These studies will help define the role of mammary adipocytes in the pathogenesis of breast cancer.
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| Park, Jiyoung; Morley, Thomas S; Scherer, Philipp E (2013) Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours. EMBO Mol Med 5:935-48 |
| Ye, Risheng; Scherer, Philipp E (2013) Adiponectin, driver or passenger on the road to insulin sensitivity? Mol Metab 2:133-41 |
| Park, Jiyoung; Scherer, Philipp E (2013) Endotrophin in the tumor stroma: a new therapeutic target for breast cancer? Expert Rev Anticancer Ther 13:111-3 |
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| Nagajyothi, Fnu; Machado, Fabiana S; Burleigh, Barbara A et al. (2012) Mechanisms of Trypanosoma cruzi persistence in Chagas disease. Cell Microbiol 14:634-43 |
| Park, Jiyoung; Sarode, Venetia R; Euhus, David et al. (2012) Neuregulin 1-HER axis as a key mediator of hyperglycemic memory effects in breast cancer. Proc Natl Acad Sci U S A 109:21058-63 |
| He, Congcong; Bassik, Michael C; Moresi, Viviana et al. (2012) Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481:511-5 |
| Park, Jiyoung; Scherer, Philipp E (2012) Adipocyte-derived endotrophin promotes malignant tumor progression. J Clin Invest 122:4243-56 |
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