Summary The level of expression of keratinocyte growth factor (KGF) mRNA has been measured in human breast cell lines, purified populations of epithelial cells, myoepithelial cells and fibroblasts from reduction mammoplasty tissue and a panel of 42 breast cancers and 30 non-malignant human breast tissues using a semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) procedure. We found similar levels of KGF mRNA in malignant and non-malignant breast tissues. The study of the amount of KGF mRNA in breast cell lines and purified populations of cells revealed that fibroblasts are the predominant source of KGF with malignant and non-malignant epithelial cells containing very low levels of KGF mRNA. We have examined the distribution of fibroblast growth factor receptor (FGFR)-2-lllb, which is a highaffinity receptor for KGF and find that it is present on malignant and non-malignant epithelial cells. The level of FGFR-2-lllb present on breast cancer cell lines was sufficient for KGF stimulation of breast cancer cell proliferation. Other members of the fibroblast growth factor family have been either not expressed in the human breast (FGF3, FGF4) or have been found at much reduced levels in breast cancer (FGF1, FGF2) and this is the first member of the family to potentially influence the progression of breast cancer through stimulation of cell division.
The expression of variant mRNAs encoding isoforms of fibroblast growth factor receptor (FGFR)1 with either 2 or 3 Ig-like loops in the extracellular domain was investigated in human breast tissues and cell lines using a polymerase chain reaction amplification method. Almost all tissues contained both forms of FGFR1, but cancers (n = 137) had a significantly lower proportion of the transcript that encoded the full 3-loop form compared with non-malignant biopsies (n = 34). This was confirmed using microdissected populations of normal and cancerous cells from frozen tissue sections. A high ratio of the 2- to 3-loop form was found to be predictive of reduced relapse-free survival. In both groups, however, the predominant form of FGFR1 was that encoding the 2-loop receptor. Cell lines derived from a variety of tissues, including breast, also co-expressed both variants of FGFR1, suggesting their presence within the same cell type. Again, there was a similar preponderance of the shorter isoform. Our results were confirmed at the protein level, where out of 5 cancers analysed 4 expressed more of the 2-loop form than the 3-loop form. Our findings suggest that cells may normally simultaneously express several splice variants of FGFR1, and aberrant expression or a change in their relative amounts (i.e., in malignancy) could contribute to modified responses to either autocrine or paracrine factors.
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