Breast Cancer is the most frequent malignancy among women worldwide. This cancer is characterized by a marked propensity for invasion and spreading through the lymphatic system, with distant metastases developing in 50-60% of cases. Human papillomaviruses (HPVs) could be important risk factors for breast carcinogenesis and metastasis, as roughly 50% of breast cancers are positive for high-risk HPVs specifically type 16 and 18. The high-risk HPV E6 and E7 oncoproteins, which are constitutively expressed in these cancers, inactivate the p53 and pRb tumour suppressors, respectively. Recently, we reported that E6/E7 of HPV type 16 converts non-invasive breast cancer cell lines, MCF7 and BT20, to invasive cells in vitro and in vivo. On the other hand, we established that E6/E7 of HPV type 16 cooperates with ErbB-2 receptor, which is over-expressed in approximately 30% of human cancers including head and neck as well as breast cancer, to induce cellular transformation of human normal oral epithelial cells. In order to study the interaction effect of high-risk HPVs infection and ErbB-2 over-expression in human breast carcinogenesis, we developed two models, in vitro and in vivo. First, we examined the effect of E6/E7 of HPV type 16 and ErbB-2 receptor in BT20 and MCF7 cell lines. We found that E6/E7 cooperates with ErbB-2 to stimulate the colony formation of these cell lines in comparison with E6/E7 and ErbB-2 alone. Second, we generated double transgenic mice (DTM) carrying E6/E7 and ErbB-2 under human keratin 14 and mouse mammary tumor virus (MMTV) promoters, respectively. These DTM develop large and extensive breast tumors within six months in comparison with E6/E7 or ErbB-2 transgenic mice within the same time period. The histological analysis of E6/E7/ErbB-2 DTM tumors revealed that these tumors are invasive (moderately to poorly differentiated carcinomas), while the breast tissues from E6/E7 and ErbB2 transgenic mice show normal and simple hyperplasia phenotype, respectively. In conclusion, we demonstrate for the first time that E6/E7 of high-risk HPVs cooperates with ErbB-2 receptor in breast cancer; this finding provide a new basis for understanding the role of high-risk HPVs infection in human breast carcinogenesis. Furthermore, our data will initiate a new therapeutic direction by co-targeting the E6/E7/ErbB-2 pathways in human breast cancer.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA