E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells

Moustafa, Ala‐Eddin Al; Foulkes, William D.; Benlimame, Naciba; Wong, A. S. Y.; Yen, Lily; Bergeron, Josée; Batist, Gerald; Alpert, Lesley; Alaoui‐Jamali, Moulay A.

doi:10.1038/sj.onc.1207148

Cited by 90 publications

(100 citation statements)

References 41 publications

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“…Although, ErbB2 inhibition with its shRNA reduced the anchorage independent growth abilities of C33A and HeLa cells, it failed to block tumor formation in nude mice (data not shown). Furthermore, HCK1T-E6E7 cells overexpressing wild type ErbB2 or constitutive active mutant (V664E) failed to form tumors (data not shown) although overexpression of HPV16 E6E7 and ErbB2 in primary oral epithelial cells has been reported to induce neoplastic transformation (Al Moustafa et al, 2004). It is possible that differences in ErbB2 expression levels or cell type are the reasons for the discrepancies.…”

Section: Chxmentioning

confidence: 95%

HPV16 E6-mediated stabilization of ErbB2 in neoplastic transformation of human cervical keratinocytes

Narisawa‐Saito¹,

Handa²,

Yugawa³

et al. 2006

Oncogene

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Whether ErbB2 receptor tyrosine kinase contributes to cervical cancer is controversial. We have examined the effects of E6 and E7 genes of human papillomaviruses type 16 (HPV-16) on ErbB2 expression in primary human cervical keratinocytes (HCK) immortalized with hTERT (HCK1T). In E6-positive cells (HCK1T-E6 and HCK1T-E6E7), ErbB2 expression levels increased with the cell density. HCK1T-E6E7 showed impaired contact inhibition and anchorage-independent growth in soft agar which were abrogated with introduction of ErbB2-specific short hairpin RNA (shRNA) or an ErbB2 specific inhibitor AG825. Furthermore, increased ErbB2 expression was also observed in HPV16 positive cervical cancer cell lines and this was diminished by introduction of HPV16E6-or E6AP-shRNA. At post-confluence cell densities, ErbB2 protein was stabilized in the presence of E6 whereas increased ErbB2 expression was not obvious with E6 mutants incapable of degrading p53. Furthermore, introduction of p53-shRNA to HCK1T resulted in increased ErbB2 protein stability, indicating possible ErbB2 regulation through p53. Finally, we showed that tumor formation of ErbB2-shRNA introduced SiHa cells were almost abolished. Taken together, these data indicate an important role of ErbB2 regulation by HPV16 E6 in oncogenic transformation of human cervical keratinocytes.

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Section: Chxmentioning

confidence: 95%

HPV16 E6-mediated stabilization of ErbB2 in neoplastic transformation of human cervical keratinocytes

Narisawa‐Saito¹,

Handa²,

Yugawa³

et al. 2006

Oncogene

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“…Immunohistochemical procedures examining the expression of Id-1 and E6 were carried out using standard procedures as previously described (Al Moustafa et al, 2004). Primary specific antibodies were obtained from Santa Cruz Biotechnology and Calbiochem.…”

Section: Immunohistochemistrymentioning

confidence: 99%

High-risk human papillomavirus infections in breast cancer in Syrian women and their association with Id-1 expression: a tissue microarray study

et al. 2008

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High-risk human papillomaviruses (HPVs) could be important risk factors for breast carcinogenesis and metastasis. Based on this hypothesis, we recently studied the effect of E6/E7 onco-proteins of high-risk HPV type 16 in two non-invasive human breast cancer cell lines, BT20 and MCF7; we reported that E6/E7 converts these cell lines to invasive cells. This is accompanied by an overexpression of Id-1, which is an important regulator of breast metastasis. In this investigation, we examined the presence of highrisk HPVs (16, 18, 31, 33 and 35) and the expression of their E6 onco-protein as well as their correlation with Id-1 gene expression, using polymerase chain reaction (PCR) and tissue microarray (TMA) analysis, respectively, in a cohort of 113 Syrian breast cancer patients. We found that high-risk HPV types 16, 18, 31, 33 and 35 are present in 8.84, 9.73, 7.07, 55.75 and 37.16% of our samples, respectively, which represent invasive breast cancers. Overall, 69 (61.06%) of the 113 samples are HPV positive; among these specimens 24 tissues (34.78%) are coinfected with more than one HPV type. Furthermore, we report that the expression of the E6 onco-protein of these high-risk HPVs is correlated with Id-1 overexpression in the majority of invasive breast cancer tissue samples. Our data suggest that high-risk HPV infections are associated with human breast cancer progression in Syrian women.

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“…These assays were performed as previously described in refs. 16 Immunofluorescence analysis. BT20 cell lines were seeded and treated with/without SKI-606 on cover-slips for two days at a density of 50,000 cells/35 mm dish.…”

Section: Methodsmentioning

confidence: 99%

“…We transduced BT20 cells with E6/E7 using a recombinant retroviral system as described previously by Al Moustafa et al in ref. 16. Next, we transduced the cell line and its wild type cells with a bicistronic retrovirus that co-expresses both ErbB-2 and enhanced green fluorescent protein (GFP-ErbB-2 and its control GFP-AP2).…”

Section: E6/e7 Of Hpv/erbb-2 Interaction In Breast Carcinogenesismentioning

confidence: 99%

“…Using this model, we demonstrated that E6/E7 cooperates with ErbB-2 receptor to induce cellular transformation of NOE via the conversion of b-catenin from a cell-adhesion molecule to a potential transcriptional regulator. 16 The objective of this project was to examine the interactive effect of ErbB-2 and high-risk HPVs infection in breast carcinogenesis. We demonstrate that the ErbB-2 receptor cooperates with E6/E7 of HPV type 16 to stimulate breast tumorigenesis, colony formation and cell migration both in vivo and in vitro, using double transgenic mice and human breast cancer cells, respectively.…”

Section: Introductionmentioning

confidence: 99%

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ErbB-2 Receptor Cooperates with E6/E7 Oncoproteins of HPV Type 16 in Breast Tumorigenesis

Yasmeen

Bismar²,

Dekhil³

et al. 2007

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/article/4949 KEY woRDsBreast tumorigenesis, transgenic mice, ErbB-2 and E6/E7 of high-risk HPV ACKnowlEDGEMEnTsWe are grateful to Drs G. Batist, M. AlaouiJamali and Foulkes for their support of this work. We are thankful to Dr. A. Darnel for his critical reading of the manuscript. We also thank Dr. T. Li-Qun and G. Mousavi for their technical assistance. This work is supported by the Canadian Institutes for Health Research (Ala-Eddin Al Moustafa) and the National Colorectal Cancer Campaign (Ala-Eddin Al Moustafa and Tarek A. Bismar). ABsTRACTThe ErbB-2 receptor is over-expressed in roughly 30% of human breast cancers. Moreover, approximately 50% of breast cancers are positive for high-risk human papillomaviruses (HPVs). Recently, we reported that ErbB-2 cooperates with E6/E7 oncoproteins of HPV type 16 to induce neoplastic transformation of human normal oral epithelial cells. We also demonstrated that E6/E7 of HPV type 16 converts noninvasive breast cancer cells to an invasive form. In order to investigate the effect of ErbB-2/E6/E7 cooperation in breast carcinogenesis, we generated double transgenic mice carrying ErbB-2 and E6/E7 of HPV type 16 under mouse mammary tumor virus (MMTV) and human keratin 14 promoters, respectively. Within six months, these double transgenic mice developed large and extensive invasive breast cancer in comparison to ErbB-2 or E6/E7 singly transgenic mice. Histological analysis of ErbB-2/ E6/E7 transgenic mice tumors showed the presence of invasive breast carcinomas. However, the breast tissues from ErbB-2 and E6/E7 transgenic mice showed only in-situ cancer and normal mammary phenotype, respectively. In parallel, we examined the cooperation effect of ErbB-2 and E6/E7 in the human breast cancer cell line, BT20; in comparison to ErbB-2 and E6/E7 alone as well as wild type cells, we found that ErbB 2/E6/E7 together stimulate colony formation and cell migration in the BT20 cell line. Furthermore, we found that b-catenin is constitutively phosphorylated by c-Src and consequently trans-located to the nucleus in ErbB-2/E6/E7-breast cancer cells. These findings provide evidence that the ErbB-2 receptor cooperates with high-risk HPVs in breast tumorigenesis via b-catenin activation.

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E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells

Cited by 90 publications

References 41 publications

HPV16 E6-mediated stabilization of ErbB2 in neoplastic transformation of human cervical keratinocytes

HPV16 E6-mediated stabilization of ErbB2 in neoplastic transformation of human cervical keratinocytes

High-risk human papillomavirus infections in breast cancer in Syrian women and their association with Id-1 expression: a tissue microarray study

ErbB-2 Receptor Cooperates with E6/E7 Oncoproteins of HPV Type 16 in Breast Tumorigenesis

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