FGFR4 Arg388 Allele Is Associated With Resistance to Adjuvant Therapy in Primary Breast Cancer

Thussbas, C.; Nährig, Jörg; Streit, Sylvia; Bange, Johannes; Kriner, Monika; Kates, Ronald; Ulm, Kurt; Kiechle, Marion; Hoefler, Heinz; Ullrich, Axel; Harbeck, Nadia

doi:10.1200/jco.2005.04.8587

Cited by 124 publications

(108 citation statements)

References 31 publications

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“…Arg 388 did not correlate with age, HER2, ER and PR status, and grade (Bange et al 2002, Jezequel et al 2004, Thussbas et al 2006, Marme et al 2010. Correlations were found for tumor stage (Thussbas et al 2006, Marme et al 2010, tumor size (Thussbas et al 2006), and axillary lymph node involvement (Bange et al 2002, Jezequel et al 2004, Thussbas et al 2006, Marme et al 2010, but not all of these associations were confirmed by other studies (Bange et al 2002, Jezequel et al 2004, Thussbas et al 2006.…”

Section: Fgfr4supporting

confidence: 77%

“…Immunohistochemical analysis of breast cancer samples did not show any correlation of the Arg 388 SNP genotype with FGFR4 expression levels (Thussbas et al 2006). Sequence analysis of breast cancer samples revealed that the Arg 388 genotype, either heterozygous or homozygous, was present in 37-43% and 8-11% respectively (Table 3; Bange et al 2002, Jezequel et al 2004, Thussbas et al 2006, Marme et al 2010.…”

Section: Fgfr4mentioning

confidence: 99%

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Fibroblast growth factor receptors in breast cancer: expression, downstream effects, and possible drug targets

Tenhagen¹,

Diest²,

Ivanova³

et al. 2012

Endocrine-Related Cancer

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Cancer treatments are increasingly focusing on the molecular mechanisms underlying the oncogenic processes present in tumors of individual patients. Fibroblast growth factor receptors (FGFRs) are among the many molecules that are involved in oncogenesis and are currently under investigation for their potential as drug targets in breast cancer patients. These receptor tyrosine kinases play a role in several processes including proliferation, angiogenesis, and migration. Alterations in these basal processes can contribute to the development and progression of tumors. Among breast cancer patients, several subgroups have been shown to harbor genetic aberrations in FGFRs, including amplifications of FGFR1, FGFR2, and FGFR4 and mutations in FGFR2 and FGFR4. Here, we review in vitro and in vivo models that have partly elucidated the molecular implications of these different genetic aberrations, the resulting tumor characteristics, and the potential of FGFRs as therapeutic targets for breast cancer treatment.

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Section: Fgfr4supporting

confidence: 77%

Section: Fgfr4mentioning

confidence: 99%

Fibroblast growth factor receptors in breast cancer: expression, downstream effects, and possible drug targets

Tenhagen¹,

Diest²,

Ivanova³

et al. 2012

Endocrine-Related Cancer

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“…Biochemically, this polymorphism influences protein stability and dysregulates FGFR4 signalling at the post-transcriptional level (Wang et al, 2008). Furthermore, expressions of certain polymorphisms or mutations have an impact on the chemosensitivity of tumours (Thussbas et al, 2006;Ansell et al, 2009). Thus, the identification of the Y367C and its consequence of an increased FGFR4 signalling provide an additional mechanism of FGFR4 perturbation that supports tumourigenic activities and hence its value as a potential drug target.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we identified a single-nucleotide polymorphism in the transmembrane domain of the FGFR4 resulting in a codon conversion from glycine to arginine (G388R), which is homologous to that in FGFR3 causing achondroplasia (Bange et al, 2002). This single-nucleotide polymorphism (SNP) is associated with increased cell motility in vitro as well as lymph node metastasis, advanced tumour stage, resistance to adjuvant therapy and therefore leading to reduced survival of cancer patients (Bange et al, 2002;Thussbas et al, 2006). These findings indicate an important role of FGFR4 in tumour biology.…”

Section: Introductionmentioning

confidence: 99%

The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells

et al. 2009

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Mutational analysis of oncogenes is critical for our understanding of cancer development. Oncogenome screening has identified a fibroblast growth factor receptor 4 (FGFR4) Y367C mutation in the human breast cancer cell line MDA-MB453. Here, we investigate the consequence of this missense mutation in cancer cells. We show that MDA-MB453 cells harbouring the mutation are insensitive to FGFR4-specific ligand stimulation or inhibition with an antagonistic antibody. Furthermore, the FGFR4 mutant elicits constitutive phosphorylation leading to an activation of the mitogen-activated protein kinase cascade as shown by an enhanced Erk1/2 phosphorylation. Cloning and ectopic expression of the FGFR4 Y367C mutant in HEK293 cells revealed high pErk levels and enhanced cell proliferation. Based on these findings, we propose that FGFR4 may be a driver of tumour growth, particularly when highly expressed or stabilized and constitutively activated through genetic alterations. As such, FGFR4 presents an option for further mutational screening in tumours and is an attractive cancer target with the therapeutic potential.

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“…FGFs serve as special players of certain carcinogenesis process due to their cell proliferating, anti-apoptotic and angiogenic properties. FGFs and FGFRs participate in skin [103] and urothelial carcinogenesis [104]. The MAPK pathway which is triggered by activation of FGFR1 has been related to the proliferation of tumor cells [105].…”

Section: Fgf and Fgfrs: Roles In Cancermentioning

confidence: 99%

Fibroblast Growth Factors and their Emerging Cancer-Related Aspects

Khalid¹,

Javaid²

2016

J Cancer Sci Ther

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FGFR4 Arg388 Allele Is Associated With Resistance to Adjuvant Therapy in Primary Breast Cancer

Abstract: According to this study, FGFR4 Arg388 genotype is a marker for breast cancer progression in patients with adjuvant systemic therapy, particularly chemotherapy, and thus may indicate therapy resistance.

Cited by 124 publications

References 31 publications

Fibroblast growth factor receptors in breast cancer: expression, downstream effects, and possible drug targets

Fibroblast growth factor receptors in breast cancer: expression, downstream effects, and possible drug targets

The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells

Fibroblast Growth Factors and their Emerging Cancer-Related Aspects

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