Human breast carcinoma desmoplasia is PDGF initiated

The desmoplastic response to human breast carcinoma is a host myofibroblast -mediated collagenous response exhibiting synergistic effects on tumor prog ression. Although many paracrine interactions between breast carcinoma cell s and myofibroblasts have been characterized, the event(s) which initiate d esmoplasia have remained undefined. Our studies utilized c-ras(H) transfect ed MCF-7 cells which overexpress ras p21 and which are weakly tumorigenic i n ovariectomized nude mice. The xenografts are desmoplastic and comprised o f 30% myofibroblasts and 60 mg/g of interstitial collagen. III sits hybridi zation studies of these xenografts reveal a stromal gene expression pattern (stromelysin-3, IGF-II and TIMP-1) identical to that observed in human tum or desmoplasia. 17-beta estradiol increases c-ras(H) MCF-7 growth but aboli shes desmoplasia. c-ras(H) MCF-7 in vitro constitutively produce myofibrobl ast mitogenic activity which competes with PDGF in a receptor binding assay . This myofibroblast mitogenic activity is unaltered by 17-beta estradiol/t amoxifen pretreatment irt vitro. Transfection of c-ras(H) MCF-7,vith a PDGF -A dominant negative mutant, 1308, produced by site-directed mutagenesis (s erine -->cystcine(129)) reduces both homo- and heterodimer secretion of PDG F by as much as 90% but does not interfere with the secretion of other grow th factors. Clones with low PDGF, though tumorigenic, are nondesmoplastic. Our results suggest that breast carcinoma-secreted PDGF is the major initia tor of tumor desmoplasia.