Tumorigenesis by mouse mammary tumor virus: Evidence for a common region for provirus integration in mammary tumors

Peters, Gordon; Brookes, Sharon; Smith, Rosalind; Dickson, Clive

doi:10.1016/0092-8674(83)90418-x

Cited by 315 publications

(161 citation statements)

References 39 publications

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“…15 Meanwhile, the FGF4 gene was first identified in gastric cancer as an oncogene HST, which has the ability to induce the neoplastic transformation of NIH-3T3 cells upon transfection. 16 These genes were initially regarded as proto-oncogenes.…”

Section: Discussionmentioning

confidence: 99%

FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma

et al. 2013

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The response rate to sorafenib in hepatocellular carcinoma (HCC) is relatively low (0.7%-3%), however, rapid and drastic tumor regression is occasionally observed. The molecular backgrounds and clinico-pathological features of these responders remain largely unclear. We analyzed the clinical and molecular backgrounds of 13 responders to sorafenib with significant tumor shrinkage in a retrospective study. A comparative genomic hybridization analysis using one frozen HCC sample from a responder demonstrated that the 11q13 region, a rare amplicon in HCC including the loci for FGF3 and FGF4, was highly amplified. A real-time polymerase chain reaction-based copy number assay revealed that FGF3/ FGF4 amplification was observed in three of the 10 HCC samples from responders in which DNA was evaluable, whereas amplification was not observed in 38 patients with stable or progressive disease (P 5 0.006). Fluorescence in situ hybridization analysis confirmed FGF3 amplification. In addition, the clinico-pathological features showed that multiple lung metastases (5/13, P 5 0.006) and a poorly differentiated histological type (5/13, P 5 0.13) were frequently observed in responders. A growth inhibitory assay showed that only one FGF3/FGF4-amplified and three FGFR2-amplified cancer cell lines exhibited hypersensitivity to sorafenib in vitro. Finally, an in vivo study revealed that treatment with a low dose of sorafenib was partially effective for stably and exogenously expressed FGF4 tumors, while being less effective in tumors expressing EGFP or FGF3. Conclusion: FGF3/FGF4 amplification was observed in around 2% of HCCs. Although the sample size was relatively small, FGF3/FGF4 amplification, a poorly differentiated histological type, and multiple lung metastases were frequently observed in responders to sorafenib. Our findings may provide a novel insight into the molecular background of HCC and sorafenib responders, warranting further prospective biomarker studies.

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Section: Discussionmentioning

confidence: 99%

FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma

et al. 2013

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“…The int-2 gene (fgf-3) was discovered because it is a main target for mouse mammary tumor virus (MMTV) insertional activation in mouse mammary tumoral cells (Peters et al, 1983;Dickson et al, 1984). The hst gene (fgf-4), ®rst identi®ed as a dominant oncogene (Delli Bovi et al, 1987), was found to be also activated in mouse mammary tumors (Peters et al, 1989) albeit at a much lower frequency than fgf-3.…”

Section: Introductionmentioning

confidence: 99%

FGF-3 and FGF-4 elicit distinct oncogenic properties in mouse mammary myoepithelial cells

et al. 1998

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Fibroblast Growth Factors 3 (FGF-3) and 4 (FGF-4) were compared for the e ects they each exert on EF43 mouse cells. This non-transformed mammary cell line appears to be myoepithelial mainly because it expresses a-smooth muscle actin. The EF43 cells were infected with similar vectors that carry either the short fgf-3 sequence (the product of which goes into the secretory pathway), fgf-4 or the selection gene only as control. In syngeneic animals, EF43.fgf-3 cells were tumorigenic only when orthotopically implanted whereas EF43.fgf-4 cells invariably gave rise to aggressive tumors. However, both tumor types were metastatic as evidenced by the blue micrometastases observed when the implanted cells expressed lacZ. In vitro, the FGF-3 producing cells were strongly invasive in matrigel coated chambers whereas the EF43.fgf-4 cells only were invasive in type I-collagen gels. Interestingly, FGF-3 production greatly stimulated the synthesis of pro-MMP-9 (Matrix Metalloprotease-9) and, to a lesser extent, that of pro-MMP-2. FGF-3 also up-regulated the production of plasminogen activators. In contrast, FGF-4 had no e ect on these secretions and the medium conditioned by the EF43.fgf-4 cells displayed the largest plasminogen activator ± inhibitor activity. These results show that FGF-3 and FGF-4 have distinct mechanisms of action on myoepithelial cells.

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“…Early studies with MMTV insertion sites revealed frequent proviral activation of members of the ®broblast growth factor (FGF) family including Fgf3 (Dickson et al, 1984;Peters et al, 1983), Fgf4 (Peters et al, 1989) and Fgf8 (Kapoun and Shackleford, 1997;MacArthur et al, 1995). Direct evidence supporting a role for these growth factors derives from studies of a number of transgenic models.…”

Section: Fibroblast Growth Factorsmentioning

confidence: 99%

Transgenic mouse models of human breast cancer

2000

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Tumorigenesis by mouse mammary tumor virus: Evidence for a common region for provirus integration in mammary tumors

Cited by 315 publications

References 39 publications

FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma

FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma

FGF-3 and FGF-4 elicit distinct oncogenic properties in mouse mammary myoepithelial cells

Transgenic mouse models of human breast cancer

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