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

Abstract

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.

High-Risk Human Papillomavirus and Colorectal Carcinogenesis

“…In parallel, we revealed that D-type cyclins (D1, D2, and D3) are essential for cell transformation induced by E6/E7/ ErbB-2 cooperation in human HNE and mouse normal embryonic fibroblast (NEF) cells [96,97]. Finally, we were able to show that the cooperation effect of E6/E7 with ErbB-2, in human normal epithelial and cancer cells, occurs via β-catenin tyrosine phosphorylation through pp60 (c-Src) kinase activation [98,99]. Thus, the cooperation between E6/E7 oncoproteins of highrisk HPVs and other oncogenes could occur in colorectal carcinogenesis.…”

Brain Metastases Progression of Breast Cancer

“…The results of other authors investigating E-cadherin involvement in brain metastasis (Arnold et al, 1999;Shabani et al, 2003;Prudkin et al, 2009) collectively demonstrate that Ecadherin is constantly expressed in metastatic deposits. Furthermore, our recent studies also demonstrated that E-cadherin-catenin complex is involved in cell migration and metastasis in vivo and in vitro (Yasmeen et al, 2007). In order to investigate the cooperation effect between ErbB-2 receptor and high-risk human papillomavirus (HPV) in breast carcinogenesis and metastasis, we generated double transgenic mice carrying ErbB-2 and E6/E7 of HPV type 16 under mouse mammary tumour virus (MMTV) and human keratin 14 (K14) promoters, respectively.…”

“…Histological analysis of ErbB-2/E6/E7 transgenic mouse tumours revealed the presence of invasive breast carcinomas. However, breast tissues from ErbB-2 and E6/E7 singly transgenic mice showed only in-situ cancer and normal mammary phenotype, respectively (Yasmeen et al, 2007). In parallel, to assess the outcome of ErbB-2/E6/E7 cooperation in human breast carcinogenesis, we examined the effect of ErbB-2 and E6/E7 of HPV type 16 on the BT20 breast cancer cell lines.…”

“…Moreover, we demonstrated that ErbB-2/E6/E7 cooperation induces a nuclear translocation of β-catenin in BT20 cells; regarding the mechanism of this translocation, we reported that ErbB-2/E6/E7 cooperation provokes a dissociation of E-cadherin/catenin complex by tyrosine phosphorylation of β-catenin through pp60(c-Src) kinase phosphorylation. Subsequently, the free β-catenin enters to the nucleus and modulates cell transcription via its association with the Tcf/Lef transcription factors (Yasmeen et al, 2007;Al Moustafa et al, 2008) (Figure 2). In conclusion, our in vitro and in vivo models demonstrated that the ErbB-2 tyrosine kinase receptor cooperates with E6/E7 of high-risk HPVs in breast tumorigenesis and metastasis via E-cadherin/catenin complex (Yasmeen et al, 2007;Al Moustafa et al, 2008).…”

“…Subsequently, the free β-catenin enters to the nucleus and modulates cell transcription via its association with the Tcf/Lef transcription factors (Yasmeen et al, 2007;Al Moustafa et al, 2008) (Figure 2). In conclusion, our in vitro and in vivo models demonstrated that the ErbB-2 tyrosine kinase receptor cooperates with E6/E7 of high-risk HPVs in breast tumorigenesis and metastasis via E-cadherin/catenin complex (Yasmeen et al, 2007;Al Moustafa et al, 2008). These studies provide evidence that MMPs and E-cadherin play an important role in brain metastases of breast cancer.…”