Abstract
The fibroblast growth factor receptor (FGFR)2 gene has been shown to be amplified in 5-10% of breast cancer patients. A breast cancer cell line developed in our laboratory, SUM-52PE, was shown to have a 12-fold amplification of the FGFR2 gene, and FGFR2 message was found to be overexpressed 40-fold in SUM-52PE cells as compared with normal human mammary epithelial (HME) cells. Both human breast cancer (HBC) cell lines and HME cells expressed two FGFR2 isoforms, whereas SUM-52PE cells overexpressed those two isoforms, as well as several unique FGFR2 polypeptides. SUM-52PE cells expressed exclusively FGFR2-IIIb isoforms, which are high-affinity receptors for fibroblast growth factor (FGF)-1 and FGF-7. Differences were identified in the expression of the extracellular Ig-like domains, acid box and carboxyl termini, and several variants not previously reported were isolated from these cells.
Highlights
The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases includes four members, all of which are highly alternatively spliced and glycosylated
In order to characterize the amplification of these candidate breast cancer oncogenes, Southern blot analysis was performed on the human breast cancer (HBC) cell line SUM-52PE and other breast cancer cell lines [14]
Because gene amplification often involves large genomic regions that contain many genes, Northern blot analysis was performed to determine whether the observed amplifications of FGFR1 and FGFR2 correlated with transcript overexpression
Summary
The FGFR family of receptor tyrosine kinases includes four members, all of which are highly alternatively spliced and glycosylated. For FGFR2, alternative splicing of the second half of the third Ig-like domain, involving exons IIIb and IIIc, is a mutually exclusive choice that affects ligand binding specificity and affinity [1,2,3]. It appears that the second half of the third Ig-like domain can dictate high affinity for FGF-2 or keratinocyte growth factor (KGF), whereas affinity for FGF-1 appears to remain the same [3]. FGFRs subsequently undergo dimerization, followed by transphosphorylation on cytoplasmic tyrosine residues [22,23]
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