Infiltrating carcinomas characteristically elicit a reactive stroma response, and accumulating evidence indicates that tumor stroma fibroblasts reciprocally promote tumor development and growth. The cell surface heparan sulfate proteoglycan, syndecan-1 (Sdc1) is thought to function as a coreceptor for growth factor and extracellular matrix interactions, and Sdc1 expression is induced in reactive stromal cells of breast carcinomas in both mice and man. Mice with a targeted mutation in Sdc1 show reduced tumor development in response to oncogene expression, and altered responses to other pathological stimuli that are associated with the induction of stromal Sdc1. Our preliminary data further demonstrate a growth-promoting loop between breast cancer cells and their stroma that depends upon the activity of Sdc1. Hypothesis: Sdc1 is a key molecule mediating epithelial-stromal interactions in breast carcinoma. Expression of Sdc1 by mesenchymal stromal cells promotes tumor growth by providing a mitogenic cue to epithelial carcinoma cells. This hypothesis will be tested by addressing the following specific aims.
Aim 1 : Determine the Sdc1 core protein requirements for stromal fibroblast-mediated carcinoma growth stimulation: The respective contribution of distinct Sdc1 core protein domains will be evaluated with a panel of deletion mutants. Sdc1-mediated stroma effects will be assessed using a physiologically relevant three-dimensional co-culture system.
Aim 2 : Characterize the molecular mechanism by which Sdc1-expressing stromal fibroblasts promote carcinoma cell growth:
This aim will examine potential mechanisms of carcinoma growth stimulation by Sdc1-expressing stromal fibroblasts. Specifically, we will investigate the role of matrix metalloproteases and heparan sulfate-dependent paracrine growth factors. The possibility that stromal Sdc1 modulates extracellular matrix assembly will also be investigated.
Aim 3 : Determine the role of stromal Sdc1 induction in breast carcinoma tumorigenesis in vivo: Stromal Sdc1 expression will be examined in human breast carcinoma samples and the contribution of stromal cell Sdc1 to carcinoma growth will be systematically evaluated in rodent models. A better understanding of the molecular mechanisms involved will help in developing therapeutic approaches designed to disrupt detrimental epithelial-stromal signaling.
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