NEW YORK CITY—The headline “Breast Cancer Linked to Mouse Virus” catches attention every few years as new findings support the hypothetical connection between a human variant of the mouse mammary tumor virus (MMTV) and human breast cancer.
Speaking here at the Chemotherapy Foundation Symposium, James F. Holland, MD, Distinguished Professor of Oncological Sciences at Mount Sinai School of Medicine in New York City, a long-time contributor to the body of knowledge on MMTV and human breast cancer, discussed recent findings in the Ezra M. Greenspan Memorial Lecture, which Dr. Holland titled “MMTV: Etiology of Breast Cancer, Fact Not Fiction.”
The search for a link goes back to 1934, he explained, when Hans Bittner discovered that MMTV, known then as the Bittner virus, was present in mice with breast cancer and later that it could cause breast cancer in healthy mice by insertional mutagenesis.
In his introduction to the talk, Symposium Chairman Franco Muggia, MD, Professor at New York University, said, “This topic could raise some controversy. We know there are many hormonal and genetic influences in breast cancer, but maybe there is an evolving story of a virus.”
Dr. Holland said that proving that a virus causes breast cancer could lead to a new concept of how to care for breast cancer, as well as other diseases such as leukemia that are also suspected of having a viral etiology.
“Potentially, viral breast cancer may have different treatments than breast cancer due to radiation, hormonal changes, or genetic abnormalities,” he said.
Anecdotal, Geographic Clues
There are many enticing clues in the history of this research. One is an anecdote Dr. Holland related, of a mouse technician working with MMTV. She had antibody titers taken routinely, and while three in a row were negative, the next was positive.
“Nine months later she developed a mass in her breast, a month after that an axillary mass, and both were found to be breast cancer,” Dr. Holland said.
Proving that an MMTV or MMTV-like viral infection was present before the patient was diagnosed with breast cancer would be a major vindication for those testing this hypothesis, that the relationship is not a myth.
Epidemiological studies already show that the presence of MMTV-like genes in humans correlates with the incidence of breast cancer.
Dr. Holland related how Paul Levine, MD, of the Department of Epidemiology and Biostatistics at George Washington University School of Public Health and Health Services, had very recently discovered that among women who have inflammatory breast cancer, 70% are positive for the virus. Other studies have shown that the virus responds to hormones, possibly explaining why breast cancer in pregnant women is relatively more virulent, Dr. Holland said.
In an earlier study, Dr. Levine showed evidence of a human breast carcinoma virus based on geographic differences in incidence, and in 2004, he reported that MMTV-like sequences were found in 74% of specimens from Tunisian women with breast cancer, compared with data from other studies showing a 36% prevalence for the US, 38% for Italy, 42% for Australia, and 0.8% in Vietnam (Cancer 2004;101:721–726).
Dr. Holland also cited work by Caroline E. Ford, then a doctoral candidate at the University of New South Wales, Australia, who found that among malignant tissues from Australian women with breast cancer, 42% were positive for MMTV-like genes, compared with only 2% of benign breast tissue taken during cosmetic surgery (Clin Cancer Res 2003;9:1118–1120).
Dr. Holland credited Robert F. Garry, PhD, Professor of Microbiology and Immunology at Tulane Medical School, with discovering a retrovirus more than 95% homologous to MMTV but endogenous to humans, called human mammary tumor virus (HMTV).
“HMTV is not present in normal tissues of breast cancer patients, and it is horizontally acquired, not genetically inherited,” Dr. Holland said.
In 2007, Dr. Holland and Beatriz G. Pogo, MD, Professor of Medical Oncology at Mount Sinai, and colleagues reported that viral particles produced in primary cultures of human breast cancer were 85% to 95% homologous with the MMTV and HMTV proviruses (Cancer Res 2007;67:8960–8965).
What Dr. Holland and colleagues need to prove now is that the viral infection occurs before the cancer. He said the hope is that a collaboration between MMTV and HMTV researchers and the Nurses' Health Study, which was started in the 1950s and is updated frequently, will answer this question.
Dr. Holland and colleagues will look at specimens taken in 1990 and 2000 from 500 women who have since developed breast cancer and from 500 controls, to determine if the frequency of virus positives is real and if it is higher in those who have breast cancer.
There is already evidence that the incidence of MMTV or a virtually homologous human virus correlates with the distribution of the agents in the environment, that it causes disease, that it is in the diseased organ and that it can be transmitted and produce a cancer.
If Nurses' Health Study data show that infections do occur before the cancer, the requirements that a virus is a causal agent in human breast cancer would be fulfilled, Dr. Holland said.
Honoring Dr. Greenspan
In his opening remarks, James Holland, MD, praised his long-time colleague the late Ezra Greenspan, MD, founder of the Chemotherapy Foundation, saying he had “a golden imagination and was a creative genius in the context of establishing a meeting such as this.”
“The most fitting obituary would have been ‘He broke the rules,’” Dr. Holland continued.
Dr. Greenspan “was the first man to use combination chemotherapy for breast cancer; the first to use combination chemotherapy for ovarian cancer; and out of his private practice, he established this symposium.”