James Lawson (JL) is from the University of New South Wales, Sydney, Australia where he established the Public Health Program. Together with his colleague Wendy Glenn and their international collaborators including Generoso Bevilacqua of Pisa and Beatriz Pogo of New York, for the past 20 years they have been investigating the viral origins of breast cancer. James has only one wife but 25 grandchildren all of whom live in Australia.
Generoso Bevilacqua (GB) served at the University of Pisa as Professor of Pathology and director of Pathology, of the PhD Course in Experimental Oncology, and of the Department of Laboratory Medicine. While at the NCI, NIH, Bethesda MD, he co-authored the discovery of the NM23 gene, the first gene with an inhibitory role in the metastasis process. His laboratory was the first one in Italy and one of the first in Europe to develop molecular pathology and the study of hereditary breast/ovarian cancer. He was co-founder and then chairman of the Group for Molecular Pathology of the European Society of Pathology. He directed national projects on molecular diagnostics and on hereditary breast/ovarian tumors of the National Research Council (CNR), the Italian Association for Cancer Research (AIRC), the Ministry of Health. He founded the Center for Hereditary Tumors of the Pisa University Hospital. He studies MMTV since the ‘70s and the possible causative role of MMTV/HBRV in human breast carcinogenesis for about 15 years. His demonstration of MMTV-like exogenous sequences in the dental calculus of individuals from the Copper Age and in human saliva helped develop the concept of the existence of HBRV, the first human betaretrovirus, present among us for thousands of years and possibly able to give origin to both neoplastic and infectious diseases.
Why is breast cancer of such concern?
JL – One in eight Western women will develop breast cancer. Most are older women but one in four are below the age of 50 many of whom have dependent children.
GB – First of all because breast cancer is a leading cause of premature death among women; when hereditary, it affects patients younger than 40 years, even at 18, 20. Moreover, the patient is affected in two very important aspects of her intimate life, breast feeding and sexuality. Breast has a special place in the collective imagination.
Why is finding the cause of breast cancer important?
JL – Despite much progress in early detection and treatment, mortality is still very high. According to the American Cancer Society, in 2021 in USA the expected new cases of invasive breast carcinoma are 284,200 with 44,130 expected deaths.
GB – I agree.
Why is finding the cause so difficult?
JL – Good question! Generoso is better able to answer than me.
GB – Human breast carcinoma is divided into two wide groups, sporadic and hereditary, each characterized by distinctly different biomolecular pathways and clinical behavior. Hereditary tumors represent 5-10% of all cases, maybe more, and are induced by highly penetrant pathogenic mutations, transmitted in an autosomal dominant way from one parent. BRCA1 and BRCA2 genes are responsible for 80-90% of cases.
For what concerns sporadic cases, whereas their pathogenesis is known in details (estrogens are the main promoting factor), their etiology remains unknown. By the way, sporadic means random, just to indicate the current lack of specific causes. This means that we don’t know the cause of 80-90% of all cases of breast cancer. All risk factors known concern the pathogenesis of disease, not its etiology. For example, obesity is a risk factor because adipose tissue is an important source of estrogens.
On the other hand, since almost one century scientists study an animal model of mammary tumors induced in mouse by the betaretrovirus Mouse Mammary Tumor Virus – MMTV. This model inspired many studies on human breast cancer and has been very useful to clarify several aspects of human cancer biology, such as the concept of cancer progression, the recognition of the preinvasive lesions and the promotional role of estrogens. Since the ‘70s, scientists try to demonstrate that MMTV is the cause of human breast cancer and in recent years data in this direction became more and more numerous. Recent studies on ancient human remnants found in Italy and on saliva of healthy people and breast cancer patients demonstrate the existence of a human betaretrovirus highly homologous to MMTV, now known as HBRV – human betaretrovirus. And the presence of viral sequences in human saliva indicates a possible inter-human diffusion by microdroplets.
Why could it not be shown that MMTV was a cause of human breast cancer?
GB – The hypothesis of a viral etiology for breast cancer goes back to the ‘70s, but only in the ‘90s the modern molecular technology allowed Beatriz Pogo and her colleagues to find MMTV sequences in human tumors. In the last almost 30 years many data confirming these observations accumulated, together with important biological data such as the demonstration that the virus can infect human breast cells. Interestingly, MMTV, now HBRV, has been shown in normal breast tissues years before the development of breast cancer and it was found absent in hereditary breast carcinomas, that, as seen above, have a specific etio-pathogenesis and do not need a virus for their development.
Why does MMTV cause breast cancer in women but rarely in men?
JL – Because men do not have enough estrogens to promote the growth of cells eventually transformed. Moreover, we have to consider that tumors of the male breast are almost all hereditary. They represent only one per cent of all breast cancers.
Why does MMTV cause cancer mainly in the breast and not other tissues?
JL – While MMTV is found in 40% of invasive breast cancers and in 80% of carcinoma in situ, it has also been identified in cancers of the uterus, prostate, ovaries and even skin. This suggests that MMTV can cause cancer in tissues influenced by sex hormones, as well demonstrated by the animal studies.
Is MMTV/HBRV involved also in non neoplastic diseases?
JL – Affirmative. Andrew Mason in Canada published several interesting papers linking the virus to a chronic inflammatory disease of liver, primary biliary cholangitis. He is also tempting a therapeutic approach to this disease (Lytvyak E …. Mason AL, Liver Int. 2021; 41(8):1879).
GB – These data strengthen our convincement that MMTV/HBRV is a human virus, by now well diffuse in the world, able to induce cancer and inflammatory disease.
We note that in their Review James Lawson and Wendy Glenn consider additional viruses which also have roles in human breast cancer. What are these viruses and are they also sex hormone dependent?
JL – The additional viruses are human papilloma virus (the cause of cervical cancer), Epstein Barr virus (the cause of some lymphomas) and bovine leukemia virus (the cause of cancer in cattle).
While these viruses probably are also influenced by hormones, it seems they are less dependent on hormones than MMTV. These viruses are present in breast cancer much more commonly than normal breast controls. While the detail is missing, it appears these viruses can interact with MMTV to cause breast cancer.
How can this new knowledge about viruses and breast cancer be used to treat and prevent human breast cancer?
JL – To discover the viral etiology of a disease open to the possibility to prevent it by vaccination. This strategy can be applied to tumors too, as demonstrated by the realization of safe and effective vaccines (Gardosil) in use to prevent infections by human papilloma viruses. The spread of bovine leukemia virus can be controlled by removal (culling/killing) infected cattle (this has already been achieved in Australia and several European countries). Experiments on experimental mice have shown that effective vaccines against MMTV are possible. It is proving very difficult to develop vaccines against Epstein Barr virus.
GB – Our colleagues in Israel have shown that it may be possible to develop vaccines against MMTV using recently developed protein based techniques.
You have both substantially contributed to this field of research. How do you feel about your work?
JL – We are very pleased. I just wish I was young again and able to see the outcomes of all our work.
GB – I am also pleased, especially on behalf of my 4,500 year old ancestors