Dual Inhibition of Both the Epidermal Growth Factor Receptor and erbB2 Effectively Inhibits the Promotion of Skin Tumors during Two-Stage Carcinogenesis

Kiguchi, Kaoru; Kitamura, Toshio; Moore, Tricia; Rumi, M.A. Karim; Chang, Hsiang Chun; Treece, Devon; Ruffino, Lynnsie; Connolly, Kevin M.; DiGiovanni, John

doi:10.1158/1940-6207.capr-10-0010

Cited by 10 publications

(9 citation statements)

References 54 publications

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“…Consistent with previous reports [40], immunohistochemistry was positive for Erbb2 in skin and in skin tumors. The receptor was localized to the cytoplasm, nucleus, and cytoplasmic membrane of skin and tumors ( Figure 2B, arrowheads indicate membrane localization).…”

Section: Erbb2 Expression Was Increased In Uv-induced Sccsupporting

confidence: 92%

Erbb2 up‐regulation of ADAM12 expression accelerates skin cancer progression

Rao

Vogel

Yanagida

et al. 2014

Molecular Carcinogenesis

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Solar ultraviolet (UV) radiation can cause severe damage to the skin and is the primary cause of most skin cancer. UV radiation causes DNA damage leading to mutations and also activates the Erbb2/HER2 receptor through indirect mechanisms involving reactive oxygen species. We hypothesized that Erbb2 activation accelerates the malignant progression of UV-induced skin cancer. Following the induction of benign squamous papillomas by UV exposure of v-ras(Ha) transgenic Tg.AC mice, mice were treated topically with the Erbb2 inhibitor AG825 and tumor progression monitored. AG825 treatment reduced tumor volume, increased tumor regression, and delayed the development of malignant squamous cell carcinoma (SCC). Progression to malignancy was associated with increased Erbb2 and ADAM12 (A Disintegin And Metalloproteinase 12) transcripts and protein, while inhibition of Erbb2 blocked the increase in ADAM12 message upon malignant progression. Similarly, human SCC and SCC cell lines had increased ADAM12 protein and transcripts when compared to normal controls. To determine whether Erbb2 up-regulation of ADAM12 contributed to malignant progression of skin cancer, Erbb2 expression was modulated in cultured SCC cells using forced over-expression or siRNA targeting, demonstrating up-regulation of ADAM12 by Erbb2. Furthermore, ADAM12 transfection or siRNA targeting revealed that ADAM12 increased both the migration and invasion of cutaneous SCC cells. Collectively, these results suggest Erbb2 up-regulation of ADAM12 as a novel mechanism contributing to the malignant progression of UV-induced skin cancer. Inhibition of Erbb2/HER2 reduced tumor burden, increased tumor regression, and delayed the progression of benign skin tumors to malignant SCC in UV-exposed mice. Inhibition of Erbb2 suppressed the increase in metalloproteinase ADAM12 expression in skin tumors, which in turn increased migration and tumor cell invasiveness.

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Section: Erbb2 Expression Was Increased In Uv-induced Sccsupporting

confidence: 92%

Erbb2 up‐regulation of ADAM12 expression accelerates skin cancer progression

Rao

Vogel

Yanagida

et al. 2014

Molecular Carcinogenesis

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“…Inhibition of TPA-induced EGFR activation in vivo , using either RG13022 (tyrosine kinase inhibitor) or GW2974 (dual specific erbB2/EGFR inhibitor) significantly reduced TPA-induced epidermal hyperproliferation as well as skin tumor promotion (GW2974) (40, 41). Additionally, epidermal IGF-1 overexpression increased epidermal proliferation, both in the presence and absence of TPA, and increased sensitivity to two-stage skin carcinogenesis (42, 43).…”

Section: Discussionmentioning

confidence: 99%

Energy Balance Modulates Mouse Skin Tumor Promotion through Altered IGF-1R and EGFR Crosstalk

Moore

Beltrán²,

Carbajal

et al. 2012

Cancer Prevention Research

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Obesity, an established risk factor for epithelial cancers, remains prevalent in the US and many other countries. In contrast to positive energy balance states (overweight, obesity), calorie restriction (CR) has been shown to act as a universal inhibitor of tumorigenesis in multiple animal models of human cancer. Unfortunately, the mechanisms underlying the enhancing effects of obesity or the inhibitory effects of CR on cancer etiology remain elusive. Here, we evaluated the impact of dietary energy balance manipulation on epithelial carcinogenesis and identified several potential mechanisms that may account for the differential effects of obesity and CR on cancer. Obesity enhanced tumor promotion during epithelial carcinogenesis, in part, due to altered IGF-1R/EGFR crosstalk and downstream signaling to effectors such as Akt/mTOR. Obesity-induced changes in cellular signaling subsequently led to altered levels of cell cycle proteins that favored enhanced epidermal proliferation during tumor promotion. In contrast, CR reduced susceptibility to tumor promotion, attenuated IGF-1R/EGFR crosstalk and downstream signaling and altered levels of cell cycle proteins that favored reduced epidermal proliferation during tumor promotion. Collectively, these findings suggest potential targets for the prevention of epithelial cancers, as well as for reversal of obesity-mediated cancer development and progression.

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“…Involvement of HER2 in CCA has been initially demonstrated by Kiguchi et al. using an excellent model of transgenic mice carrying the human HER2 gene in combination with exposure of the bile acid .…”

Section: Expression Profile Of Cca In Thailand and Japanmentioning

confidence: 99%

“…On the other hand, molecules of the HER2 cascade could serve as possible molecular targets for the diagnosis and treatment of CCA not associated with Ov infection. Involvement of HER2 in CCA has been initially demonstrated by Kiguchi et al using an excellent model of transgenic mice carrying the human HER2 gene in combination with exposure of the bile acid [16,17].…”

Section: Expression Profile Of Cca In Thailand and Japanmentioning

confidence: 99%

Genomic and transcriptional alterations of cholangiocarcinoma

Ito

Sakurai-Yageta

Goto

et al. 2014

J Hepato Biliary Pancreat

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Cholangiocarcinoma (CCA) is one of the representative cancers refractory to any therapeutic approach. The incidence of CCA is highest in the northeastern part of Thailand, where chronic inflammation caused by liver fluke (Opisthorchis viverrini: Ov) infection is a major etiologic factor. The incidence of CCA is also increasing in other countries, including Japan. Here, we overview the genetic and transcriptional alterations of CCA with and without association with Ov infection. CCA with Ov shows enhanced expression of the genes involved in xenobiotic metabolism and chronic inflammatory responses, including cytokine signaling, whereas CCA without Ov shows enhanced expression of growth factor signaling, such as HER2. Exome and the following prevalence sequencing identified mutations of the BAP1, ARID1A, IDH1 and IDH2 genes in CCA, in addition to the high incidence of known mutations in the TP53, KRAS2 SMAD4, and CDKN2A genes, suggesting the role of chromatin modulators in CCA pathogenesis. CCA with Ov shows significantly higher incidence of the TP53 gene mutation, whereas CCA without Ov showed significantly more frequent mutations of the BAP1, IDH1 and IDH2 genes. However, CCAs with Ov and without Ov share a similar mutation spectrum dominated by C : G > T : A transitions mainly at CpG dinucleotides, suggesting that CCA shares etiologic factors with pancreatic ductal carcinoma but not with hepatocellular carcinoma. Comprehensive analyses of the genetic and transcriptional alterations of CCA with and without Ov infection would provide useful information for the prevention, early diagnosis, and treatment of CCA.

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Dual Inhibition of Both the Epidermal Growth Factor Receptor and erbB2 Effectively Inhibits the Promotion of Skin Tumors during Two-Stage Carcinogenesis

Cited by 10 publications

References 54 publications

Erbb2 up‐regulation of ADAM12 expression accelerates skin cancer progression

Erbb2 up‐regulation of ADAM12 expression accelerates skin cancer progression

Energy Balance Modulates Mouse Skin Tumor Promotion through Altered IGF-1R and EGFR Crosstalk

Genomic and transcriptional alterations of cholangiocarcinoma

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