Cloning and characterization of an androgen-induced growth factor essential for the androgen-dependent growth of mouse mammary carcinoma cells.

Tanaka, Akira; Miyamoto, Kaoru; Minamino, Naoto; Takeda, Masatoshi; Sato, Bunzo; Matsuo, Hisayuki; Matsumoto, Keīichi

doi:10.1073/pnas.89.19.8928

Cited by 363 publications

(245 citation statements)

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“…Previous studies in hormone-related cancers (prostate and breast cancers), as well as esophageal cancer demonstrated that FGF8b gene expression was regulated by androgen/testosterone (Tanaka et al, 1992(Tanaka et al, , 2001Gnanapragasam et al, 2002). Given the relatively higher expression levels of FGF8b mRNA in male NPC tumors ( Figure 1A), we examined if androgen (in the form of testosterone) was responsible for FGF8b regulation in EBV-associated NPC cells.…”

Section: Nf-kb Is An Upstream Regulator Of Fgf8b Expression In Ebv-asmentioning

confidence: 93%

“…FGF8 is known to be essential for embryogenesis (Crossley and Martin, 1995), in particular, for the development/organogenesis of the craniofacial, pharyngeal, brain, cardiac, kidney, urogenital organs and limbs (Heikinheimo et al, 1994;Crossley et al, 1996;Mattila and Harkonen, 2007). Investigation on the involvement of FGF8b in hormone-related cancers was indeed based on the initial discovery of FGF8 (androgen-induced growth factor) in an androgen-dependent mouse mammary carcinoma cell line (Tanaka et al, 1992) and detection of FGF8 overexpression in human breast and prostate cancers (Tanaka et al, 1995;Leung et al, 1996;Gnanapragasam et al, 2002). Further genomic and functional characterization of the FGF8 family demonstrated that the FGF8b isoform (one of the four human FGF8 isoforms: FGF8a, b, e and f (Gemel et al, 1996)) possesses the greatest mitogenic and, more importantly, the greatest transforming activity than the other isoforms, both in vitro and in vivo (MacArthur et al, 1995a(MacArthur et al, , 1995bBlunt et al, 1997;Song et al, 2000;Olsen et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Owing to the original discovery of FGF8 in an androgen-dependent system (Tanaka et al, 1992), as well as cumulative findings that FGF8b knockin mice developed prostate and breast cancers, investigations on the role of FGF8b in human oncogenesis have primarily been focused on hormone-related cancers. Clinical studies revealed that FGF8b overexpression was found in the majority of prostate cancer (40-80%) (Dorkin et al, 1999;Gnanapragasam et al, 2002Gnanapragasam et al, , 2003Tanaka et al, 2002;Zhong et al, 2006) and breast cancer (B70-100%) .…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, its overexpression was clinically associated with disease progression (mainly staging and grading), poor prognosis, poor survival (Dorkin et al, 1999;Valve et al, 2001), and potentially metastasis in prostate cancer (Gnanapragasam et al, 2003;Valta et al, 2008). Although the molecular mechanisms for FGF8b overexpression in prostate and breast cancers are not fully understood, the human sex hormone androgen (Tanaka et al, 1992) is known to play a key role, even in the case of breast cancer (Castellano et al, 2010Park et al, 2010 (in addition to prostate cancer (Gnanapragasam et al, 2002)). Similar findings in esophageal cancer, which has recently found to be androgen-related (Yamashita et al, 1989;Awan et al, 2007;Thaver et al, 2009), also revealed that FGF8b overexpression is linked to androgen signaling (Tanaka et al, 2001;Awan et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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FGF8b oncogene mediates proliferation and invasion of Epstein–Barr virus-associated nasopharyngeal carcinoma cells: implication for viral-mediated FGF8b upregulation

et al. 2010

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The fibroblast growth factor 8b (FGF8b) oncogene is known to be primarily involved in the tumorigenesis and progression of hormone-related cancers. Its role in other epithelial cancers has not been investigated, except for esophageal cancer, in which FGF8b overexpression was mainly found in tumor biopsies of male patients. These observations were consistent with previous findings in these cancer types that the male sex-hormone androgen is responsible for FGF8b expression. Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer of head and neck commonly found in Asia. It is etiologically associated with Epstein-Barr Virus (EBV) infection, inflammatory tumor microenvironment and relatively higher male predominance. Here, we reported for the first time that FGF8b is overexpressed in this EBV-associated non-hormone-related cancer of the head and neck, NPC. More importantly, overexpression of FGF8b mRNA and protein was detected in a large majority of NPC tumors from both male and female genders, in addition to multiple NPC cell lines. We hypothesized that FGF8b overexpression may contribute to NPC tumorigenesis. Using EBV-associated NPC cell lines, we demonstrated that specific knockdown of FGF8b by small interfering RNA inhibited cell proliferation, migration and invasion, whereas exogenous FGF8b stimulated these multiple phenotypes. Further mechanistic investigation revealed that in addition to NF-jB signaling (a major inflammatory signaling pathway known to be activated in NPC), an important EBV oncoprotein, the latent membrane protein 1 (LMP1), was found to be a direct inducer of FGF8b overexpression in NPC cells, whereas androgen (testosterone) has minimal effect on FGF8b expression in EBVassociated NPC cells. In summary, our study has identified LMP1 as the first viral oncogene capable of directly inducing FGF8b (an important cellular oncogene) expression in human cancer cells. This novel mechanism of viral-mediated FGF8 upregulation may implicate a new role of oncoviruses in human carcinogenesis.

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Section: Nf-kb Is An Upstream Regulator Of Fgf8b Expression In Ebv-asmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

FGF8b oncogene mediates proliferation and invasion of Epstein–Barr virus-associated nasopharyngeal carcinoma cells: implication for viral-mediated FGF8b upregulation

et al. 2010

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“…Most FGF proteins are secreted and their e ects as extracellular components are mediated by a complex system of FGF receptor (FGFR) tyrosine kinases either through autocrine or paracrine mechanisms (Basilico and Moscatelli, 1992;Johnson and Williams, 1993;Mason, 1994;Coulier et al, 1997;Verdier et al, 1997). FGF8 was originally isolated from the conditioned medium of an androgendependent Shionogi mouse mammary carcinoma, SC-3, cell line (Tanaka et al, 1992). The expression of this growth factor has been correlated with murine embryogenesis in gastrulation, regionalization of the brain, and organogenesis of limbs, face and tail bud (Crossley and Martin, 1995;Heikinheimo et al, 1994;Ohuchi et al, 1994;Mahmood et al, 1995;Crossley et al, 1996).…”

mentioning

confidence: 99%

Downregulation of human FGF8 activity by antisense constructs in murine fibroblastic and human prostatic carcinoma cell systems

et al. 1998

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Previously, we described cloning of three alternatively spliced mRNA forms of human FGF8, a, b, and e, of which the b form is the major expressed species in both normal and tumor prostatic epithelial cells. In this report, we describe construction and overexpression of sense and antisense sequences of either the full length FGF8b coding region (215-amino acids or 215aa), 103aa N-terminal part or a smaller N-terminal region (34aa), each including the 23aa putative signal peptide domain, via a retrovirus system. While the morphologic transforming activities of the sense 215aa and 103aa constructs were similar in NIH3T3 cells, 103aa displayed reduced soft agar clonogenic activity. The 34aa construct was practically inert in these assays, although its expression could mimic the ability of 215aa or 103aa in conferring cell growth under reduced serum condition. Overexpression of any of the three constructs in antisense orientation, however, was similarly e ective in reversing the morphology and anchorage-independent growth property of FGF8b-transfected NIH3T3 cells. The expression of the antisense 215aa construct signi®cantly reduced the growth rate of the human prostatic carcinoma DU145 cells and inhibited their soft agar clonogenic activity and in vivo tumorigenicity in nude mice. Taken together, these results identify Nterminal portions of FGF8 protein isoform for having the domains necessary for one or more of the biologic e ects examined, and suggest that low levels of FGF8 expressed in prostatic epithelial cells may contribute signi®cantly to their growth and tumorigenic properties.

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Genomic structure, sequence, and mapping of humanFGF8 with no evidence for its role in craniosynostosis/limb defect syndromes

et al. 1997

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Fibroblast growth factor-8 (Fgf8) is a recently identified growth factor that stimulates the androgen-dependent growth of mouse mammary carcinoma cells. Evidence from mouse development also shows that Fgf8 may play an important role in growth and patterning of limbs, face, and the central nervous system. We describe here the human FGF8 genomic sequence and demonstrate conservation between the human and mouse sequences, including alternatively spliced exons in the mouse. Mapping of FGF8 by FISH using an FGF8-containing bacterial artificial chromosome and by genetic linkage using a SSCP variant identified in this study is also reported and refines the FGF8 map location to 10q24. Since FGF8 maps to the same chromosomal region as FGFR2, has indeed been shown to be a ligand for FGFR2, and has an expression pattern consistent with limb and craniofacial anomalies, we have screened two kindreds with Pfeiffer syndrome that were previously linked to markers from 10q24-25 and a large number of individuals with craniosynostosis and limb anomalies for mutations in the coding sequence of FGF8. While no such mutations were identified, a rare polymorphic variant, consisting of an 18-base-pair (six-amino-acid) duplication in exon 1c, is reported that apparently has no clinical effect. Our exclusionary data suggest that mutations in FGF8 would be, at best, an infrequent cause of such disorders.

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Cloning and characterization of an androgen-induced growth factor essential for the androgen-dependent growth of mouse mammary carcinoma cells.

Abstract: An androgen-dependent mouse mammary carcinoma cell line (SC-3) requires androgen for growth stimulation. We have shown previously that androgen acts on SC-3

Cited by 363 publications

References 26 publications

FGF8b oncogene mediates proliferation and invasion of Epstein–Barr virus-associated nasopharyngeal carcinoma cells: implication for viral-mediated FGF8b upregulation

FGF8b oncogene mediates proliferation and invasion of Epstein–Barr virus-associated nasopharyngeal carcinoma cells: implication for viral-mediated FGF8b upregulation

Downregulation of human FGF8 activity by antisense constructs in murine fibroblastic and human prostatic carcinoma cell systems

Genomic structure, sequence, and mapping of humanFGF8 with no evidence for its role in craniosynostosis/limb defect syndromes

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