Breast tumour cell-induced down-regulation of type I collagen mRNA in fibroblasts

This study investigated the modulation of type I collagen gene expression i n normal fibroblasts by breast tumour cells. Northern analysis of total RNA extracted from stages I, II and III breast tumour tissue revealed that col lagen mRNA levels were elevated in stage I tumours compared to the adjacent normal breast tissues, whereas they were decreased in stages II and III br east tumours. This aberrant collagen gene expression was confirmed by non-r adioactive RNA:RNA in situ hybridization analysis of 30 breast carcinomas w hich localized the production of type I collagen mRNA to the stromal fibrob lasts within the vicinity of the tumour cells, In order to determine whethe r the tumour cells were directly responsible for this altered collagen prod uction by the adjacent fibroblasts, breast tumour cell lines were co-cultur ed with normal fibroblasts for in vitro assessment of collagen and steady-s tate collagen RNA levels, Go-culture of tumour cells and normal fibroblasts in the same dish resulted in down-regulation of collagen mRNA and protein. Treatment of the fibroblasts with tumour-cell conditioned medium also resu lted in decreased collagen protein levels but the mRNA levels, however, rem ained unaltered. These results suggested that the tumour cells either secre te a labile 'factor', or express a cell surface protein requiring direct co ntact with the fibroblasts, resulting in down-regulation of collagen gene e xpression. Modulation of the ECM is a common characteristic of invading tum our cells and usually involves increased production of collagenases by the tumour cells or stromal fibroblasts. This study showed that tumour cells we re also able to modulate collagen mRNA production by stromal fibroblasts, w hich may facilitate tumour cell invasion and metastasis. (C) 1999 Cancer Re search Campaign.