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Vol. 05 Issue 3, Early Fall 2000

Search for Viral Involvement in Human Breast Cancer
The Ribbon 

Bonnie B. Asch, Ph.D., Division of Experimental Pathology,
Roswell Park Cancer Institute Corp., Buffalo, NY

The idea of a virus playing a role in human breast cancer originated with the discovery of Mouse Mammary Tumor Virus (MMTV). The suspicion that a virus might cause or in some way contribute to human breast cancer became firmly established with the discovery that a virus present in certain mice caused breast cancer in about 90% of the infected females. However, research to make the transition from suspicion to proven fact has been a long, arduous task that is still far from finished. The mouse virus was designated MMTV and has been under intensive study since the 1930's. This virus has many interesting properties and has been an invaluable tool for scientists who are investigating the cause and mechanism of breast cancer development. In infected mice, MMTV reproduces in breast epithelial cells and makes numerous copies of itself. Under standard conditions, infection by MMTV does not occur in adult mice. For example, uninfected adult female mice do not become infected with MMTV even when they are housed for many months with infected mice and are in constant, direct contact with them (Moore and Holben, 1978). Instead, MMTV is passed in the milk of an infected mother to her young during nursing. Infection can be prevented by transferring the mouse pups to an uninfected foster mother before they nurse from their birth mother. Once infection occurs, the animal remains infected throughout life. Tumors begin appearing when the mice are about 6 months of age or older (reviewed in Asch, 1996).

MMTV is a retrovirus, which is a RNA tumor virus that contains a protein called reverse transcriptase. This protein is essential for both the ability of the virus to infect a cell and the ability of the virus to cause a tumor (Asch, 1996). When MMTV invades a cell, it uses reverse transcriptase to make a DNA copy of itself. The DNA form of the virus becomes incorporated into the DNA of the infected cell. When it inserts into cell DNA, the virus causes a mutation by adding extra DNA and disrupting the normal sequence of the cell's genetic material. MMTV does not contain any oncogenes (genes that can cause cancer) in its DNA. The virus initiates the development of breast cancer by activating oncogenes present in normal breast epithelial cells of infected mice. This happens because the insertion of viral DNA into cell DNA often occurs near an oncogene (Asch, 1996). The activity of an oncogene is normally regulated very tightly by a cell so that cell growth is carefully controlled. If an oncogene becomes overactive in a cell, then uncontrolled growth can occur which eventually might lead to formation of a cancer. This is the proposed consequence of oncogene activation by MMTV in a cell.

MMTV-related material is detectable in many human breast cancers. Two possibilities have been explored to determine MMTV's potential role in human breast cancer. The first theory is that humans are often exposed to MMTV because infected house mice live very close to us and occasionally, the virus is able to infect a person, eventually enter breast epithelial cells, become integrated into the cell's DNA, and start the sequence of events which will change the normal cells into cancer cells. The second possibility is that a human version of MMTV exists (human mammary tumor virus) which is similar, but not identical, to MMTV, and can cause cancer by the same method as the mouse virus (Wang et al., 1995). To investigate these possibilities, several approaches have been taken, including studies to identify MMTV-like virus particles in human breast cancer tissue and cells, surveys to detect MMTV proteins in breast cancer tissues and cells and to detect antibodies against these proteins in breast cancer patients, analyses to find DNA sequences of such a virus in DNA of human breast cancers (Wang et al., 1995), and most recently, an epidemiological study to compare the distribution of MMTV-infected mice with the incidence of breast cancer in various regions of the world (Stewart et al., 2000) (see Research Commentary). The results of these studies have been provocative (reviewed and discussed in Stewart et al., 2000). MMTV-like virus particles have been identified in breast cancer tissues and cells, MMTV proteins and antibodies against them were found in breast cancer patients, DNA sequences closely related to MMTV sequences have been detected in about 40% of breast cancer DNA samples examined (Wang et al., 1995), and a high breast cancer incidence correlated with geographical regions where house mice populations are high (Stewart et al., 2000). MMTV-related sequences and proteins have not been found in normal breast tissue near the positive tumors.

Is the evidence for a MTV conclusive or circumstantial? While the above findings justify continued studies on MMTV as a suspect in the origin of some breast cancers, they do not provide conclusive evidence that a MMTV or its human equivalent has a causal role in the human disease. The key question thenis, what would constitute such evidence? The gold standard for determining if a particular biological agent, whether it is bacterial, fungal, viral, etc., is responsible for causing a certain disease, is that criteria called "Koch's postulates" must be fulfilled. Koch's postulates consist of the following requirements for the agent: 1) it must be present in every case of the disease; 2) it must be isolated from the diseased tissue, e.g. breast cancer, and grown in culture to obtain sufficient quantities for testing; 3) when a sufficient amount of a pure preparation of the agent is inoculated into a healthy test animal, the disease must develop; 4) it must be reisolated from the diseased tissue that develops in the test animal (the test animal, of course, is not going to be human). With certain agents like viruses, these criteria are difficult or impossible to meet. All viruses require living cells to grow, so they cannot grow alone in pure culture. Even with a culture of living cells, many viruses, including MMTV, grow poorly or not at all. If a virus were isolated, grown in cell culture, and sufficient quantities were obtained and inoculated into a test animal, it might not produce the disease if it is a virus that can only infect and grow in humans. The cause of more than 90% of breast cancers is unknown, but many scientists think there is probably more than one cause of the disease. Some cancers might result from exposure to a particular environmental chemical, others from some type of hormonal abnormality, and perhaps others from a virus. If this were true, then the virus would not be present in every case of the disease. Thus, there are problems with all of Koch's postulates in applying them to investigating the role of MMTV or a human MTV in breast cancer. For the present, then, the evidence is circumstantial.

Other viral candidates that might have a role in breast cancer. In addition to MMTV, other viral suspects are also under investigation, including Epstein-Barr virus (EBV) and bovine leukemia virus (BLV). EBV is a human tumor virus associated with various types of lymphomas and some nasopharyngeal carcinomas. The first report suggesting a possible link of EBV with human breast cancer was published in 1995 by British scientists (Labrecque et al., 1995), who detected EBV sequences in DNA from 21% of 91 different breast cancers and found EBV RNA in several of them as well. Two subsequent studies by other investigators failed to find evidence of EBV in their series of breast cancers, but a more recent study done in France (Bonnet et al.,1999) detected EBV DNA sequences in 51% of breast cancers analyzed. EBV sequences were not detected in normal breast tissue of the patients. BLV causes leukemia in cows, and can infect human cells in culture. Research on BLV's potential relationship with breast cancer has been pursued by Dr. Gertrude Buehring and her collaborators (Buehring et al., 1994; Buehring et al., 1998). This virus is present in many cattle and in beef and dairy products consumed by humans. Dr. Buehring has found BLV protein in epithelial cells of some human breast tissue samples and antibodies specific for a BLV protein in blood samples of about half of the humans tested (Buehring et al., 1994; Buehring et al., 1998). The mechanisms by which EBV and BLV cause cancer are different from that of MMTV and are poorly understood. The evidence suggesting either EBV or BLV initiates or has some other type of role in human breast cancer is even weaker than that supporting such a role for MMTV or its human counterpart.

In summary. Currently available information puts each of these viruses at the "crime scene" of breast cancer. Proof beyond a reasonable doubt that one or the other of them had anything to do with the "crime", i.e. development of breast cancer, however, will require substantial additional evidence. This evidence can only be obtained through further research.

References

Asch, B.B. "Tumor viruses and endogenous retrotransposons in mammary tumorigenesis." J. Mammary Gland Biol. Neoplasia 1 (1996):49-59.

Bonnet, M., J-M. Guinbretiere, E. Kremmer, V. Grunewald, E. Benhamou, G. Contesso, I. Joab. "Detection of Epstein-Barr virus in invasive breast cancers." J. Natl. Cancer Inst. 91 (1999):1376-1381.

Buehring, G.C., P.M. Kramme, R.D. Schultz. "Bovine leukemia virus (BLV) in breast tissue and antibodies to BLV in human sera." Anticancer Res. (1998).

Buehring, G.C., P.M. Kramme, R.D. Schultz. "Evidence for bovine leukemia virus in the mammary epithelial cells of infected cows." Lab. Invest. 71 (1994):359-365.

Labrecque, L.G., D.M. Barnes, I.S. Fentiman, B.E. Griffin. "Epstein-Barr virus in epithelial cell tumors: A breast cancer study." Canc. Res. 55 (1995):39-45.

Moore, D.H., J.A. Holben. "Observations on the question of horizontal transmission of mouse mammary tumor virus." Canc. Res. 38 (1978):2455-2457.

Stewart, T.H.M., R.D. Sage, A.F.R. Stewart, D.W. Cameron. "Breast cancer incidence highest in the range of one species of house mouse, Mus domesticus." British J. Cancer 82 (2000):446-451.

Wang, Y., J.F. Holland, , I.J. Bleiweiss, S. Melana, X. Liu, I. Pelisson, A. Cantarella, K. Stellrecht, S. Mani, B.G.T. Pogo. "Detection of mammary tumor virus ENV gene-like sequences in human breast cancer." Canc. Res. 35 (1995):5173-5179.

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Last Update 08.23.00