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Molecular Biology and Genetics |
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, D-82152 Martinsried, Germany [J. B., Y. C., T. K., S. M., S. G., I. S., P. K., A. U.]; Departments of Pathology [D. P., H. H.] and Obstetrics and Gynecology [N. H., M. S.], Technical University of Munich, D-81675 Munich, Germany; Department of Pathology, Gesellschaft für Strahlenforschung, D-85764 Neuherberg, Germany [K. S., H. H.]; The Eastern Hepatobiliary Surgery Institute, 200438 Shanghai, People’s Republic of China [H. W.]; N. N. Petrov Institute of Oncology, 189646 St. Petersburg, Russia [E. I., P. K.]; Medical Clinic Department IV, Eberhard-Karls-University of Tubingen, D-72076 Tubingen, Germany [H-U. H.]; and Department of Oncology, University of Chieti, 66100 Chieti, Italy [S. I.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Besides the imbalance in regulatory pathways due to changes in gene expression, functional alterations in key proteins caused by gene mutations contribute to the manifestation of pathological phenotypes. In general, a distinction can be made between sequence variants with functional consequences for the encoded protein that predispose to pathological syndromes and common sequence variations, which represent functionally neutral genetic markers. Great efforts are under way to identify such SNPs and, in connection with clinical data, establish correlations with disease susceptibility, progression, and/or response to therapeutic regimens (12) .
Alterations in RTK genes such as specific point mutations or gene amplification were found to induce neoplastic disorders (13 , 14) , as first demonstrated for the oncogenic activation of HER2 (15) and its rat homologue, p185neu (16) . More recently, achondroplasia and Crouzon syndrome, two forms of human dwarfism, have been shown to be caused by G380R and A391E amino acid substitutions in the transmembrane domain of FGFR3 (17 , 18) . Moreover, a recent study revealed somatic mutations in the FGFR3 and FGFR2 genes in human bladder, cervical, and colorectal carcinomas (19 , 20) , further emphasizing the relevance of FGFR family sequence alterations for human pathological disorders.
The four closely related human FGFRs and their more than 20 known ligands control a multitude of cellular processes, including cell growth, differentiation, and migration, and it has been shown that the FGF/FGFR system plays a critical role in cancer development due to its angiogenic potential or direct enhancement of tumor growth (21) . For example, autocrine growth stimulation through the coexpression of FGF and FGFR in the same cell results in the transformation of Balb/c 3T3 cells (22) . Moreover, translocation of FGFR1 and FGFR3 genes was shown to be associated with leukemia and multiple myeloma (23 , 24) , and in prostate cancer cells, FGFR1 signaling was found to be critical for cell growth (25) .
The study presented here began with the investigation of mRNA expression levels of phosphotyrosine signaling system components by cDNA array hybridization analysis of breast cancer cell lines, with the aim of identifying new targets for the development of therapeutic strategies. We identified a novel allele of the FGFR4 gene, and screening of cancer patients and normal blood donors characterized this sequence difference at codon 388 as a frequently occurring germ-line SNP. This SNP is present at significantly higher frequency in cancer patients with aggressive disease progression and therefore represents a gene alteration that predisposes the carrier to poor clinical outcome.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Two control groups of healthy Caucasian individuals without personal history of cancer were chosen to determine the distribution of the FGFR4 G388R conversion in the general population.
Cell Lines.
All cell lines except DAL (provided by Dr. G. Natali) and Ac 745 (provided by Sugen Ltd., Redwood City, CA) were obtained from the American Type Culture Collection (Manassas, VA) and grown as recommended by the supplier.
cDNA Array Hybridization.
Total RNA, Poly(A)+ RNA, and cDNA probes were generated as described elsewhere (27)
. Labeling of 3–5 µl of cDNA was performed with the Megaprime kit (Amersham) in the presence of 50 µCi of [
-32P]dATP. The prehybridization solution was replaced by the hybridization solution containing 5x SSC, 0.5% (v/v) SDS, 100 µg/ml baker yeast tRNA (Roche), and the labeled cDNA probe (2–5 x 106 cpm/ml) and incubated at 68°C for 16 h. Membranes were washed under stringent conditions. A phosphorimager system (Fuji BAS 1000; Fuji) was used to quantify the hybridization signals. Average values for each slot were calculated using the formula: A = (AB - B) x 100/B; [A, final volume; AB, intensity of each slot signal (pixel/mm2); B, background (pixel/mm2)].
Real-Time RT-PCR Analysis.
Quantitative real-time RT-PCR was performed using the ABI PRISM 7700 Sequence Detection System instrument and software (Applied Biosystems, Foster City, CA). The FGFR4-specific primers were 5'-TCCGCTGGCTTAAGGATGG-3' and 5'-CACGAGACTCCAGTGCTGATG-3', and the fluorogenic probe was 5'-6-carboxy-fluorescein-AACCGCATTGGAGGCATTCGG-6-carboxy-tetramethyl-rhodamin-3'. Amplification of PGK (phosphoglycerokinase) as an endogenous reference was performed to standardize the amount of sample RNA. PGK primers and probes were purchased from Applied Biosystems. PCR was carried out with the TaqMan Universal PCR Master Mix (Applied Biosystems) using 50 ng of cDNA, 200 nM probe, 900 nM forward primer, and 300 nM reverse primer in a 30-µl final reaction mixture. The cycling conditions consisted of an initial incubation at 50°C for 2 min, followed by 10 min at 95°C and 50 cycles of 15 s at 95°C, and 1 min at 60°C. Experiments were performed in duplicate for each sample, and the amounts of FGFR4 and PGK mRNAs were determined from a standard curve consisting of 5-fold serial dilutions of MDA-MB-361 cDNA (100 to 0.016 ng).
Sequence Analysis of FGFR4.
cDNAs from the cell lines MDA-MB-453 and K562 were amplified with primers designed to amplify the coding region of the FGFR4 (5'-GAATTCGCCACCATGCGGCTGCTGCTGGCCCTG-3', 5'-GCCTCGAGTCATGTCTGCACCCCAGACCCGAA-3') and to sequence the FGFR4 extracellular, transmembrane, and intracellular domains (primers: 5'-GAGGAAGTGGAGCTTGAG-3', 5'-GGCACGAGGCTCCATGAT-3', 5'-GCGCCATCAGCACTGGAG-3', 5'-GCAAGTCCTAAAGACTGC-3', 5'-CAGGGCCGGCACCCCCGC-3', 5'-GCCAGGTAGTACGTGCAG-3', 5'-GCCCCGACCTCAGCCCCG-3', 5'-TGACCGGGTGTACACACA-3', and 5'-GCTGGAAACGGTCCTGCT-3'. For RFLP analysis, cDNA and genomic DNA were prepared as described elsewhere (27)
. To screen individuals for FGFR4 Arg388 allele, the following primers were designed: 5'-GACCGCAGCAGCGCCCGAGGCCAG-3' and 5'-AGAGGGAAGAGGGAGAGCTTCTG-3'. Primers (2 µM) and 50 ng of cDNA or genomic DNA were combined in a 25-µl total reaction volume using Ready-to-Go PCR beads (Pharmacia, Uppsala, Sweden). The 168-bp fragment was digested overnight with BstNI (NewEngland BioLabs) according to the manufacturer’s instructions. Restriction fragments were resolved on a 12% nondenaturing polyacrylamide gel, and DNA was visualized with ethidium bromide. The Arg388 allele was characterized by two distinctive fragments of 82 and 27 bp, whereas a single distinctive band of 109 bp was observed for the Gly388 allele.
Retroviral Gene Transfer in Cell Lines.
Human FGFR4 cDNA was amplified and subcloned into the Bluescript I KS vector as described above. FGFR4 Arg388 was generated by in vitro mutagenesis (27)
. Both cDNAs were cloned into the pLXSN vector. The packaging cell line Phoenix A was transfected with these vectors using calcium phosphate. The supernatant of transfected Phoenix A cells was collected and filtered through a 0.45-µm filter. For the infection of the human breast cancer cell line MDA-MB-231, cells were incubated with viral supernatant for 24 h. After 48 h, medium was replaced with medium containing 400 µg/ml G418. For further selection, cells were incubated with G418 for 14 days. Monoclonal cell lines were generated by limited dilution. FGFR4 expression was monitored by Western blot analysis. Four monoclonal cell lines with similar expression levels of FGFR4 Gly388 and FGFR4 Arg388 were chosen for further experiments.
Wounding Assay of Scatter/Migration.
Cells were grown to confluence in 60-mm-diameter culture dishes in standard medium and analyzed using a classical scratch wound method. Cells were gently scraped with a plastic tip. The medium was removed, and cells were washed twice with PBS. Medium or medium with 0.5% FCS was added, and the cells were permitted to scatter/migrate into the area of clearing for 24 h.
Statistical Methods.
Statistical evaluations were performed using the MedCalc statistics package (MedCalc Software) and WinStat. The frequencies of the genotypes among different subgroups were calculated by P to assess the association between FGFR4 Arg388 and malignancy in the volunteers. Because of their small number, FGFR4 Arg388 homozygotes were grouped together for analysis with heterozygotes and treated as carriers for analysis. Survival curves for disease-free survival were plotted according Kaplan-Meier and compared using log-rank statistics. All tests were performed at a significance level of = 0.05.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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shows representative autoradiographs of cDNA arrays hybridized with probes of two breast cancer cell lines. Whereas most of the PTPs and PTKs have comparable expression levels in the breast cancer cell lines (data not shown), the FGFR4 gene was one that exhibited striking variations (Table 1)
. The amount of FGFR4 transcripts ranged from undetectable in five breast cancer cell lines and all normal cell lines to very high in six breast cancer cell lines. To confirm the cDNA array data for FGFR4, we performed Northern blot and TaqMan quantitative RT-PCR analysis. FGFR4 levels coincided in most cases with the expression profile obtained through cDNA array hybridization experiments (Table 1
; data not shown). It is noteworthy that inconsistent expression profiles were obtained for some cell lines. However, we believe that these variations are largely due to technical problems and/or that the selection of the primers causes a bias against certain unspliced forms of transcripts.
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A), resulting in the substitution of a valine residue for an aspartate (29)
. Interestingly, a novel missense mutation changing codon 388 (GGG) to AGG (Fig. 2A)
resulting in a proteotype change from Gly to Arg (G388R) in the FGFR4 transmembrane domain (Fig. 2B)
was identified in all clones analyzed.
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A mutation in codon 388 created a new BstN1 restriction site, genotyping was done by PCR-RFLP analysis (Fig. 3A)
. Of the 21 cell lines tested, 8 were found to have the BstN1 restriction site and therefore express the FGFR4 Arg388 allele. The overall frequency was 58% for homozygous Gly alleles, 31.5% for heterozygous Gly/Arg alleles, and 10.5% for homozygous mutant Arg alleles (Table 1)
. Interestingly, in many cases, breast cancer cell lines that display an Arg allele as either Gly/Arg or Arg/Arg show high FGFR4 gene expression, whereas cell lines homozygous for FGFR4 Gly388 exhibit weak or no FGFR4 gene expression, with the exception of BT-474 (Table 1
; P = 0.0017, cDNA array; P = 0.01, TaqMan RT-PCR; Mann-Whitney test). These data suggested that the FGFR4 Arg388 allele and increased FGFR4 expression are associated with breast cancer development.
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. A similar allele distribution was found in 84 breast cancer patients of German origin. Forty-one patients (47%) had homozygous Gly/Gly alleles, 34 (42%) had heterozygous Gly/Arg alleles, and 9 (11%) had homozygous Arg/Arg alleles (Table 2)
. Most importantly, PCR-RFLP analysis of genomic DNA from peripheral WBCs of 10 of the Russian patients revealed the same genotype as seen in the tumor tissue, demonstrating that the GA conversion at codon 388 is defined by a germ-line polymorphism (Fig. 3B)
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2 = 0.21; P = 0.64; data not shown). Therefore, both groups were combined for further analysis. Among the control DNAs, 55 (45%) had homozygous Gly/Gly alleles, 60 (49%) had heterozygous Gly/Arg alleles, and 8 (6%) had homozygous Arg/Arg alleles (Table 2)
. Similar results were obtained from a third study of healthy Chinese individuals (data not shown). The Gly388 allele is represented in the majority of the population and is therefore referred to as FGFR4 wild type, whereas FGFR4 mutant denotes the Arg allele. This definition is supported by the fact that charged amino acids normally do not occur in the transmembrane domain of RTKs and have previously been found to be associated with diseases such as achondroplasia and Crouzon syndrome. When the genotype distribution between breast cancer patients and controls was compared, no significant difference was revealed (2 = 3.55; P = 0.17; Table 2
), indicating that Arg388 is not associated with the initiation of cancer before the average age of reproduction.
In the clinically well-documented Munich cohort, we then investigated the impact of the FGFR4 Arg388 allele on breast cancer progression by comparing clinicopathological parameters and FGFR4 genotypes. As shown in Table 3
, no correlation was observed between the FGFR4 Arg388 allele and pathological parameters such as age at diagnosis, tumor stage, and estrogen receptor levels. A positive trend, which failed to reach significance, was found regarding patients with FGFR4 Arg388 and axillary lymph node involvement. In some cases, the FGFR4 Arg388 allele coincided with the HER2 overexpression status in tumors, but there was no consistency in this regard (Table 3
; data not shown). Studies are ongoing to examine a possible cooperative function of HER2 and FGFR4 Arg388 in a larger set of patients.
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). Because of the small number of patients with two FGFR4 Arg388 alleles, Gly/Arg and Arg/Arg carriers were combined for further survival analysis. No significant effect was found in patients without axillary lymph node involvement (Fig. 4B)
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. Thirty-seven patients (45%) had Gly/Gly alleles, 38 (46%) had Gly/Arg alleles, and 7 (9%) were Arg/Arg allele carriers. As shown in Table 4
, there was a statistically significant correlation between the FGFR4 Arg388 allele and both metastatic lymph nodes (P = 0.0016) and advanced tumor-node-metastasis (TNM) stage (P = 0.03), indicating an association between the FGFR4 Arg388 allele and advanced disease progression. Kaplan-Meier survival analysis of the colon cancer patients stratified for the FGFR4 allele distribution yielded no clear cut result for a follow-up time of 7 years but revealed a significantly reduced overall survival for FGFR4 Arg388 carriers over a 16-month follow-up period (P = 0.02; Fig. 4C
). Taken together, the colon cancer patient analysis supports the results of our analysis of the breast cancer cohort and strongly suggests that the association of the FGFR4 Gly/Arg388 alleles with advanced disease is not restricted to the cancer types investigated in this study.
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and protein levels. MDA-MB-231 cells were infected with a recombinant retrovirus containing cDNA sequences encoding either the Gly388 or Arg388 FGFR4 allele. Four clones stably expressing one or the other receptor allele were chosen to determine the capacity of cells to migrate and scatter randomly in a patch wound repair assay. Migration of the cells during wound closure was studied after scraping cells from an area in a confluent monolayer of cells. Interestingly, in comparison with parental MDA-MB-231 cells, the closure rate was decreased in cell cultures overexpressing FGFR4 Gly388 when assayed 24 h after wounding. In contrast, control virus-infected cells or cells expressing FGFR4 Arg388 migrated in a scattered fashion into the wound (Fig. 5)
. We also observed that cells expressing FGFR4 Gly388 grew tightly connected to each other, whereas cells expressing FGFR4 Arg388 or control virus-infected cells migrated individually and had assumed a more fibroblastic spindle-like morphology (data not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the present study, we examined the expression levels of genes that are linked to phosphotyrosine-mediated signaling in breast cancer cell lines to identify further targets for the development of novel therapeutics. cDNA array hybridization and quantitative RT-PCR analyses showed that FGFR4 is strongly expressed in 30% of breast cancer cell lines, but not in normal cell lines. These results are compatible with those of previous studies, which demonstrated high FGFR4 expression in pancreatic cancer (30) , breast cancer (31 , 32) , and renal cell carcinoma (33) , without providing any insights into the pathophysiological and clinical significance of these observations.
The major finding of this study is the identification of a sequence polymorphism in codon 388 of the human FGFR4 gene, which generates receptors with either a glycine or an arginine at this position in the transmembrane domain of FGFR4, a general hot spot in RTKs for disease-related sequence variations. For example, sporadic and germ-line-transmitted mutations in the transmembrane domain of FGFR-2 and FGFR-3, which are rare in the general population, are connected to distinct forms of developmental disorders of the skeleton (17 , 18) . In contrast, the Arg388 form of FGFR4 is a common sequence variant that appears to be present in about 50% of the general population. Nevertheless, our statistical analysis clearly shows that the Arg388 allele is significantly overrepresented in the group of breast cancer patients with axillary lymph node involvement and early relapse. Together, these findings lead to the conclusion that the FGFR4 Arg388 allele is causally connected to aggressive tumor progression but has no role in tumor formation. In addition, the fact that breast cancer patients in late stages (pN1/2) could be further subdivided by FGFR4 Arg388 allele status in patients with better or worse clinical outcome suggests this polymorphism as a discrimination factor within the conventional stage definition. Studies are ongoing to examine this hypothesis on a larger patient cohort with longer follow-up data.
In patients with colorectal cancer, clinicopathological parameters such as lymph node involvement and tumor stage were clearly correlated with the FGFR4 Arg388 allele, which demonstrates that this genotype is a critical determinant not only in breast cancer but also in colon cancer progression. Moreover, colon cancer patients with the FGFR4 Arg388 allele showed a clear trend to reduced overall survival, which was particularly evident during the first 16 months of the follow-up period. In the group of FGFR4 Arg388 carriers, 15 of 45 patients had died in this period in comparison with the group of homozygote Gly388 patients (n = 37), in which only 5 patients had died (P = 0.02; log-rank test). These data, together with the observed association of FGFR4 Arg388 with clinicopathological parameters, demonstrate that the FGFR4 Arg388 allele has an accelerating impact on disease progression in human colorectal cancer.
The biochemical consequence of the G388R conversion in the FGFR4 receptor for expressing cells is not completely understood. Similar to the GA nucleotide substitution in codon 380 of the FGFR3 gene, the mutation results in a charged amino acid in the highly conserved transmembrane region. Analogous missense mutations in the transmembrane domain of RTKs, such as neu resulting in the replacement of hydrophobic amino acids with a charged one, were previously proposed to result in increased tyrosine kinase activity (34)
. Under our experimental conditions, however, we were unable to detect any enhanced tyrosine kinase activity of the FGFR4 Arg388 receptor isotype in transfected cells after FGF stimulation (data not shown), which suggests that the activation properties of FGFR4 are only subtly changed in the Arg388 version of the receptor. In this regard, it is intriguing that a common genetic ValIle polymorphism in the transmembrane domain of the HER2 gene, which is likely to have less impact on receptor domain structure than the FGFR4 GlyArg conversion, has been linked to an increased risk for breast cancer in a population-based case-control study in China (35)
, further supporting a role of RTK polymorphisms in cancer development and progression. Based on these data, one can argue that genetic alterations will only persist in the human genome when their effects are weak and will only modulate certain traits predisposing the individual for specific diseases or changes in clinicopathological parameters.
In spite of our inability to demonstrate biochemically detectable effects on the kinase activity in the Arg388 form of FGFR4, MDA-MB-231 cells expressing Gly388 and Arg388 receptors were clearly distinct with respect to morphology and motility. Local invasion, intravasation, extravasation of tumor cells, and angiogenesis all require cell movement. In addition, it was reported that reduced intercellular adhesion, accompanied by higher motility and invasiveness of the tumor cells, is a consequence of the loss of epithelial differentiation in carcinomas (36) . Therefore, it appears that the decreased motility of MDA-MB-231 cells expressing FGFR4 Gly388 is caused by increased adhesion to either the substratum or neighboring cells. It is intriguing in this context that FGFR1 can be activated by a number of cell adhesion molecules like N-cadherin, L1, and N-CAM via special binding motifs as shown in several reports (37) . Most of the motifs involved in these interactions are conserved in FGFR1, FGFR2, and FGFR4. Interestingly, we have observed that Cos7 and PC12 cells can adhere to culture dishes coated with the FGFR4 extracellular domain.3 Hence, it is most likely that FGFR4 can interact with other membrane-anchored proteins on the same or neighboring cell and function as either a ligand or a receptor. A recent report by Cavallaro et al. (38) indicates that in a mouse tumor model, cell-matrix interaction and metastasis of pancreatic ß-cell tumors are regulated by a N-CAM/FGFR4 signaling complex. Interestingly, reduced N-CAM expression was associated with increased malignancy and poor prognosis in a variety of cancer types (39) , and Rip1Tag2 transgenic mice, which develop ß-cell tumors in the pancreatic islets of Langerhans, show a marked increase in tumor metastases when crossed with N-CAM knockout mice (40) . Therefore, Cavallaro and colleagues speculate that N-CAM has the potential to prevent the dissemination of metastatic tumor cells via the FGFR4. Moreover, loss of N-CAM in the Rip1Tag2 transgenic mouse model of ß-cell carcinogenesis results in the formation of metastases mainly in the draining lymph nodes of the pancreas (41) . In this regard, it is interesting to note that in our study, patients with colon cancer showed an association between the FGFR4 Arg388 allele and an increased number of lymph node metastases (P = 0.0016). Thus, the difference in adhesion and motility properties of MDA-MB-231 FGFR4 Gly388 and Arg388 cells and the association between poor clinical outcome of cancer patients with the FGFR4 Arg allele might involve the disruption of a complex between FGFR4 and cell adhesion molecules due to a change in receptor conformation as the result of a charged amino acid within the transmembrane domain replacing a neutral glycine residue.
Our findings further expand the understanding of the pathophysiological potential of RTKs and suggest a scenario in which the action of a dominant oncogene and loss of critical tumor suppressor functions may play key roles in the cancer initiation phase, eventually leading to the activation of FGFR4 gene transcription. At this point, the FGFR4 genotype has a decisive impact and ultimately defines, in concert with other genetic and circumstantial determinants, the diversity of individual cancer progression. Additional studies will elucidate the importance of the highly abundant Arg388 allele for other cancer types and possibly for other pathological conditions.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be addressed, at Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, D-82152 Martinsried, Germany. E-mail: ullrich{at}biochem.mpg.de 
2 The abbreviations used are: PTK, protein tyrosine kinase; FGFR, fibroblast growth factor receptor; PTP, protein tyrosine phosphatase; RT-PCR, reverse transcription-PCR; SNP, single-nucleotide polymorphism; RTK, receptor tyrosine kinase; DFS, disease-free survival; N-CAM, neural cell adhesion module; FGF, fibroblast growth factor.
3 J. Bange, unpublished observations.
Received 8/29/01. Accepted 11/30/01.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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