10.2217/17460913.1.1.33 © 2006 Future Medicine Ltd ISSN 1746-0913 Future Microbiol. (2006) 1(1), 33–51 33 PERSPECTIVE Viruses and human breast cancer James S Lawson † , Walter H Günzburg & Noel J Whitaker † Author for correspondence School of Public Health, University of New South Wales, Sydney, Australia Tel.: +61 298 794 221; James.Lawson@unsw.edu.au Keywords: breast cancer, Epstein–Barr virus, etiology, hormones, human papilloma virus, mouse mammary tumor virus, nutrition, viruses There are well-established risk factors for breast cancer, most of which relate to estrogens and growth hormones in females. These include early-age menarche, late-age menopause, postmenopausal obesity and use of hormone therapy. However, these factors do not account for the sixfold difference in breast cancer incidence and mortality between countries and the fact that these differences dramatically lessen after migration; nor do they account for male breast cancer. Accordingly, hormone-responsive viruses have become major suspects as etiological agents for human breast cancer. Human papillomaviruses, mouse mammary tumor virus and Epstein–Barr virus are the prime candidate viruses as causes of human breast cancer. Human papillomaviruses and the mouse mammary tumor virus have hormone responsive elements that appear to be associated with enhanced replication of these viruses in the presence of corticosteroid and other hormones. This biological phenomenon is particularly relevant because of the hormone dependence of breast cancer. Viral genetic material for each of these candidate viruses has been identified by polymerase chain reaction in breast tumors but rarely in normal breast tissue controls. Pooled data from controlled studies show substantial odds ratios for the presence of viral genetic material in breast tumors compared with normal controls. These and additional data provide substantial, but not conclusive, evidence that human papillomavirus, the mouse mammary tumor virus and Epstein–Barr virus may have a role in the etiology of human breast cancer. If conclusive evidence for a role of these viruses in breast carcinogenesis can be developed, there is a practical possibility of primary prevention. John Bittner and others at the Jackson Laborato- ries in Maine, ME, USA, discovered a factor transmitted by mothers’ milk that caused mam- mary tumors in both field and experimental mice 70 years ago [1]. This was later shown to be the mouse mammary tumor virus (MMTV). This discovery raised the obvious question: could simi- lar viruses cause human breast cancer? An intense period of research followed in the post World War II decades, and a number of inconclusive observations were made. These included the iden- tification of electron microscopic images of viruses in human mother’s milk that appeared to have similar characteristics to MMTV [2] and the detection of MMTV glycoprotein-52 cross-reac- tive proteins in tumor tissue of women with breast cancer [3]. Unfortunately, these and other studies [4–6] proved highly controversial – the elec- tron microscopic images being likened to milk aggregates and the cross-reactive proteins being found both in healthy and in breast tumor-bear- ing women, albeit with different frequencies, sug- gesting that the antibodies used might cross-react with cellular proteins [7]. Further studies in the 1980s investigated the presence of antibodies cross-reactive to MMTV antigens in patient’s sera. Again, although some studies reported a positive correlation [8,9], these studies were highly controversial [10,11] since the correlations shown were far from absolute. Antigen- and antibody-based studies were gradually replaced by molecular biological investigations during the 1980s. Initially it seemed easy to demonstrate DNA sequences cross-hybridizing with MMTV sequences in human breast tumors [12], but it was soon real- ized that the normal human genome also con- tained similar sequences [13,14]. These sequences were later designated as human endogenous retroviruses (HERVs) and shown to make up more than 1% of the human genome [15,16]. Prior to nucleic acid sequencing, it was difficult to distinguish between MMTV and HERV sequences and many scientists left the field to pursue other interests. A quiet and largely unrecognized change to this climate of disinterest began in the early 1990s. Human papilloma virus (HPV) sequences were identified in human breast tumors and it was shown that some of these women with HPV-asso- ciated breast cancer also had the same high-risk HPV type associated cervical cancer [17,18]. Epstein–Barr viral (EBV) sequences were identi- fied in human breast tumors but rarely in normal For reprint orders, please contact: reprints@futuremedicine.com