Human papilloma virus as causal in breast cancer.

The aim of this review is to consider the role of high-risk human papillomaviruses (HPVs) in breast cancer. HPVs have established causal roles in cancers of the cervix, anus, penis, vagina, vulva, and oropharyngeal cancers. High-risk HPVs have been consistently detected in breast cancers in 23 countries. HPVs have been identified in 32.7% of breast cancers as compared to 7.6% of benign and normal breast controls. HPV-positive benign breast lesions can progress to HPV-positive malignancies, suggesting an early role of HPVs in carcinogenesis. HPV biological activity has been demonstrated by the detection of HPV transcripts, HPV oncogenic protein expression (HPV E6/E7), and HPV-induced koilocytes in breast cancer tissues. HPVs sourced from normal breast tissues and human milk can immortalise normal cultured breast epithelial cells. There is a plausible mechanism for the transfer of HPV material from the genital tract and cervix to the breast via blood and circulating exosomes. HPV-associated breast cancer is probably via a "hit and run" causal mechanism. The influence of HPV vaccination in reducing the incidence of breast cancer by 18% to 19% offers supportive evidence of causation. Other oncogenic viruses, including mouse mammary tumour virus, Epstein-Barr virus, and bovine leukaemia virus, may contribute to breast carcinogenesis independently or synergistically with high-risk HPVs. The evidence meets the extended Bradford Hill causal criteria. High-risk HPVs probably have a causal role in a subset of breast cancers.