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Vol. 05 Issue 3, Early Fall 2000

Is there a Breast Cancer Causing Virus in Humans?
The Ribbon 

Susan R. Ross, Ph.D., Professor of Microbiology, Cancer Center,
University of Pennsylvania Medical Center, Philadelphia, PA

Exciting advances have been made in recent years in understanding the genetics of breast cancer in humans. Scientists have identified several inherited genes that predispose women to breast or ovarian cancer, but these probably only account for five to 10 percent of the cases (Szabo and King, 1997). Understanding the causes of sporadic breast cancer is therefore of major importance. It has long been known that an infectious virus, called mouse mammary tumor virus (MMTV), causes breast cancer in mice. Recent findings have implicated a similar type of viral agent in human breast cancer. In this article, I discuss what is known about how MMTV is transmitted and causes cancer in mice and whether it is likely that a similar agent exists in humans.

MMTV was first identified in the 1920's, when it was found that a breast cancer-causing agent was passed through milk from mothers to daughters in mice (Bittner, 1936). This transmissible agent caused almost 100% of these daughters to develop breast cancer. But when the newborn daughters of mice from a strain with a high rate of breast cancer were nursed by foster mothers from a strain that had a low rate of breast cancer, the virus was not transmitted and the daughters did not develop breast cancer. The only clearly established mode of transmission of infectious MMTV is through milk. Even when housed in the same cage, the virus is not passed from MMTV-infected to uninfected mice. MMTV is probably transmitted most efficiently via breast milk because of the extremely high levels of virus found in milk in comparison with, for example, blood, saliva or seminal fluid and with the increased susceptibility of newborns to infection with viruses in general.

MMTV was the first virus shown to cause cancer in mammals. Many other viruses have now been shown to cause cancer in mammals, including humans. Some of the more common viruses are Epstein Barr virus, which causes infectious mononucleosis in Western populations, but is associated with human nasopharyngeal carcinomas in Asia and lymphomas in Africa; the recently discovered Kaposi's Sarcoma Herpes Virus found in individuals with AIDS; and leukemia viruses, such as feline leukemia virus (FeLV) and human T cell leukemia virus I (HTLV I). These latter viruses (FeLV and HTLV I), as well as MMTV and HIV (human immunodeficiency virus), all belong to the class of viruses called retroviruses. Retroviruses share the same replication pathway; that is, their genes are encoded in ribonucleic acid (RNA) molecules in the virus. After they infect a cell, this RNA molecule gets converted into a deoxyribonucleic acid (DNA) molecule which then integrates into or becomes part of the cell's chromosomes. The DNA codes for viral proteins that are needed to make more viruses. With retroviruses like HIV, which gets into the white blood cells that are needed to fight off infections, there are virus proteins made in infected cells that have deleterious effects, leading to their death. Many other retroviruses, however, have little or no effect on the cells when they integrate into the chromosome, although the cells now become virus-producers. In some cells, when the virus integrates into the chromosome near genes involved in the regulation of cell growth, it activates those genes. The normal cell then turns into a cancer cell, and starts dividing until it becomes a tumor.

For MMTV, this type of cancer-causing integration into the chromosome occurs only in mice that are highly infected and produce very large amounts of virus. This is because the likelihood that the virus will integrate next to and activate a gene involved in the cell's growth regulation is very small. We know, for example, that some mice are genetically resistant to MMTV infection and as a result, never get MMTV-induced breast cancer even though small amounts of virus are found in their mammary glands. In mice that do develop breast cancer caused by this virus, almost every mammary gland cell gets infected.

Another important factor in the ability of this virus to cause breast cancer is the number of times the mouse gets pregnant. MMTV first infects the mammary gland during puberty, getting into a number of target cells that are dividing under the influence of hormones such as estrogen. If infected mice never get pregnant, they have about a 50% chance of developing MMTV-induced breast cancer. However, if they are allowed to go through several pregnancies, this chance increases to almost 100%. This is because MMTV best infects cells that are dividing and the cells of the mammary gland divide every time an animal becomes pregnant to maximize milk production after birth. So mice that go through several pregnancies have many more MMTV-infected cells than virgin mice. As a result, there is a greater likelihood that the virus will make a cancer-causing insertion into the chromosome.

Might a similar type of virus exists in humans? After the identification of the actual MMTV virus particle in the 1970's, there were a number of publications that reported finding MMTV-like proteins in breast cancer biopsies and antibodies against the mouse virus proteins in human breast cancer patients (Day et al., 1981; Levine et al., 1984). However, there were no reports of finding genetic material in human breast milk that was similar to MMTV's RNA nor could any viral DNA be found in the tumor cells that was unique to breast cancer patients.

In recent years, very sensitive techniques have been developed that allow the detection of minute amounts of either DNA or RNA. These techniques have been used to reexamine the issue of whether MMTV-like genetic material is present in human breast cancer. Several research groups have reported that more than 30% of human breast cancer samples contain DNA that highly resembles MMTV (Wang et al., 1995; Etkind et al., 2000). In contrast, normal mammary gland and other tissues did not have this DNA. This has sparked some renewed interest in the idea that some human breast cancer is caused by a virus similar to that found in the mouse.

How likely is it that breast cancer is caused by a MMTV-like virus in humans? Based on what we know about the mouse virus, we would expect that pregnancy should increase cancer rates. However, in epidemiological studies, pregnancy has been shown to have a protective effect on the development of human breast cancer (Kampert et al., 1988). Another prediction is that breast-fed daughters of mothers who went on to develop breast cancer would themselves be at higher risk. Instead, breast cancer rates have gone up at the same time that breast feeding rates have decreased (MacMahon et al., 1973). Moreover, several epidemiological studies have shown no increased incidence of breast cancer in daughters who were nursed by mothers that later developed breast cancer (Titus-Ernstoff et al., 1998; Ekbom et al., 1993). However, these studies all rely on self-reported data, which in the case of breast-feeding that occurred decades before the development of cancer, may be inaccurate. Additionally, if we draw analogies from MMTV, virus transmission would occur only early on in breast feeding; the time period of nursing was not addressed in the studies. Nonetheless, we know that similar types of virus can be transmitted in humans by breast feeding. In Japan, it has clearly been established that breast milk is the major source of HTLV I transmission even though not all children get infected (Ichimaru et al., 1991; Saji et al., 1990). Indeed, HTLV I infection rates have been dramatically reduced by encouraging infected mothers to bottle-feed their children (Hino et al., 1997).

Thus, there is no epidemiological support for a milk-borne, MMTV-like-induced breast cancer in humans. Recently it has also been suggested that this virus could be transmitted directly from mice to humans. This "zoonotic" mode of infection was proposed because it was shown that geographic areas of high breast cancer incidence, namely Western Europe and North and South America, overlap with the distribution of the Mus domesticus species of house mouse (Stewart et al., 2000) (see Research Commentary). Other regions of the world, where breast cancer incidence is lower, have other species of wild mice, such as the Mus musculus species predominantly found in Eastern Europe. Both Mus musculus and Mus domesticus carry infectious MMTV, however (reviewed in Stewart et al., 2000). The authors conclude that if there was zoonotic transmission of MMTV, only the Mus domesticus version could jump the species barrier.

Can we conclude from these various studies that there is a MMTV-like virus associated with human breast cancer? As it currently stands, this conclusion is problematic. Given that in mice, the species in which the virus is found, the only major mode of transmission is through milk, it is hard to imagine the mechanism by which the virus would jump from mice into humans. Furthermore, we know from laboratory studies that MMTV does not readily infect human cells (Howard and Schlom, 1980; Golovkina et al., 1998; our own unpublished observations). Because there is no indication from the epidemiological studies that there is passage of the virus from mothers to daughters through nursing, such a zoonotic transmission would have to be occurring at a very high rate to account for the presence of a MMTV-like virus in greater than 30% of human breast cancers. Thus, this means that not only would the virus have to mutate to be infectious in humans, but it would have to be transmitted in a completely novel mode.

However, one of the surprising observations made about the MMTV-like viruses found in human breast cancer samples was how closely related they are to the mouse virus (Wang et al., 1995; Etkind et al., 2000). What is even more surprising is that the part of the virus that was found in the human breast cancers is the gene for a viral protein (the envelope protein) that determines whether the virus can enter a cell. If a mouse virus had mutated so that it now was capable of infecting human cells, one would expect the greatest differences between the mouse and the human virus to be in the envelope protein and yet, the published human virus envelope gene is almost identical to that of the mouse virus.

Furthermore, if a MMTV-like virus were involved in human cancer, we would expect it to be readily detectable not only in the tumor tissue, but in the normal breast tissue. This is because MMTV causes cancer by infecting many cells until it accidently integrates into a gene involved in cell growth regulation, as described above. Yet, human breast cancer samples have such low levels of the MMTV-like virus that only extremely sensitive methods could detect it (Wang et al., 1995; Etkind et al., 2000). In the few cases where normal breast tissue was obtained from the same individual who had a tumor, no MMTV-like virus DNA could be detected at all in the normal tissue (Wang et al., 1995). Finally, we know that the only way that MMTV can infect mammary gland cells in mice is if their white blood cells get infected first (see Fig. 1) (Tsubura et al., 1988; Golovkina et al., 1998) and yet no MMTV-like sequences were detected in the blood cells of breast cancer patients.

So, while the recent data implicating a human MMTV-like virus in breast cancer is tantalizing, the current evidence argues against such an agent. If there were such a virus, it would have to infect humans in a dramatically different way than does MMTV in mice. In this case, it is hard to explain the high degree of similarity between the recently identified human virus and MMTV. Much more data are needed to show that such an agent exists.

References

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