Bovine Leukemia Virus Infection and Human Breast Cancer Risk

Institution: University of California, Berkeley
Investigator(s): Gertrude  Buehring , Ph.D. -
Award Cycle: 2000 (Cycle VI) Grant #: 6PB-0075 Award: $187,414
Award Type: Request for Applications
Research Priorities
Prevention & Risk Reduction>Other searches for the causes



Initial Award Abstract (2000)
The purpose of the research proposed here is to determine whether infection of a woman's breast tissue with bovine leukemia virus (BLV) makes it more likely that she will develop breast cancer. Our interest in this question stems from the fact that breast cancer in the mouse is caused by a virus, MMTV, which is transmitted from mother to nursing baby mice via the milk. The MMIV system provides proof that a naturally occurring cancer can be caused by a virus in a food source. Since the main source of milk for humans is cows, a bovine virus might be a likely candidate for a milk-transmitted agent of human breast cancer.

Bovine leukemia virus (BLV)is a cancer causing virus of cattle which can be transmitted from cow to calf via the milk. BLV commonly infects dairy and beef cattle and is found in the marketed milk and meat of these animals. Most infected cattle are healthy and are not removed from the herd. Consumption of non-pasteurized dairy products or undercooked beef could possibly allow transmission of infectious virus to humans. BLV can infect other species including sheep and goats naturally, and several species experimentally including non-human primates. BLV can also infect the cells of many species cultured in flasks, including cells from humans and other primates. We recently discovered that BLV infects the breast cells of cows naturally and causes these cells to behave more like cancer cells. This indicates that this "leukemia" virus can target more than just blood cells.

Our preliminary data suggests that humans can become infected with BLV. We found 53% of the humans tested have antibodies to BLV in their blood, which is an indication of exposure to BLV. We also detected BLV proteins and DNA in human breast tissues removed by surgery, which suggests these tissues were infected by BLV. The research proposed here is to ascertain whether the presence of BLV DNA and proteins in breast tissues correlates with the patient's diagnosis of breast cancer. Breast cancer tissues from 10 women and normal tissue from 169 controls with no history of breast neoplasms will be tested by in situ-polymerase chain reaction for proviral BLV DNA and by immunohistochemistry for BLV capsid protein. The association between the presence of BLV DNA/protein and patient diagnosis will be analyzed statistically. If frequency of BLV infection is shown to be significantly different in malignant breast tissue versus normal controls, this will justify the launching of a larger prospective study designed to determine whether BLV can cause some cases of breast cancer. The ultimate impact of the project could be to reduce breast cancer incidence by preventing human infection with BLV through elimination of the virus in cattle, interception of its transmission from cattle to humans, or vaccinations of humans.


Final Report (2002)
The purpose of this funded research is to determine whether infection of a woman's breast tissue with bovine leukemia virus (BLV) makes it more likely that she will develop breast cancer. Bovine leukemia virus (BLV) is a cancer-causing virus of cattle which infects dairy and beef cattle and is found in the marketed milk and meat of these animals. Consumption of unpasteurized dairy products or undercooked beef could possibly allow transmission of infectious virus to humans. Our previous studies suggest that humans can become infected with BLV: 77% of the humans we tested had antibodies to BLV in their blood, and we detected BLV proteins and DNA in human breast tissues removed by surgery, which suggests these tissues were infected by BLV. The specific aims of this research were to collect 169 samples each of normal breast tissue (from women with no history of breast cancer) and malignant breast tissue, test them for the presence of BLV DNA and proteins, and see if the presence of the virus correlated with the patient's diagnosis of breast cancer. The association between the presence of BLV DNA/protein and patient diagnosis would be analyzed statistically. Samples positive for BLV DNA would be sequenced to determine variation among the BLV strains infecting different humans.

During the total grant period we collected 75 tissues and completed the tests for the virus genetic material for 51 of these specimens. We have worked out the procedure for sequencing the BLV DNA from positive specimens and have sequenced the BLV isolated from 3 donors. It was similar to the published sequence of BLV providing support that what we have detected is truly BLV. We have set up a spreadsheet in a statistical program and have entered the data we have collected on the 51 completed specimens.

The frequency of BLV infection in malignant breast tissue was higher than in normal controls, but we were not able, during this grant period, to obtain and analyze enough specimens to match each malignant tissue with a normal tissue from a donor of the same age. Thus, we are not yet able to determine whether the difference in frequency of BLV in malignant versus normal breast tissue is statistically significant. Upon the eventual completion of this project, the ultimate impact could be to reduce breast cancer incidence by preventing human infection with BLV through elimination of the virus in cattle, interception of its transmission from cattle to humans, or vaccination of humans.


Symposium Abstract (2005)
We cannot hope to control breast cancer without knowing its cause. Breast cancer in mice is caused by a milk-transmitted virus, MMTV, and provides a model for a viral cause of human breast cancer. Since humans drink more cows milk than human milk, a bovine virus might be involed in human breast cancer. Bovine leukemia virus (BLV) causes widespread infection of cattle globally and in 1-5% of infected cattle leukemia/lymphoma may develop. Most infected cattle remain healthy, are retained in the herd, and are sources of beef and dairy products. Infectious virus may be present in bovine foodstuffs not adequately cooked or pasteurized. BLV infects white blood cells and breast cells of cattle. It can cross species naturally to infect goats and sheep, and can infect human cells in culture. Evidence is accumulating that some humans are infected with BLV. Antibodies to BLV were detected in 74% of human volunteers. BLV protein and DNA have been detected in human breast epithelium. The purpose of this case-control study was to determine whether BLV DNA is present more frequently in the breast tissue of women with a diagnosis of breast cancer than in women who have never had breast cancer. This is a first step in determining whether BLV in breast tissue is a risk factor for developing breast cancer. Breast tissues were obtained through the Cooperative Human Tissue Network from four catchment areas, Philadelphia, PA, Columbus, OH, Birmingham, AL, and the San Francisco East Bay area. Breast tissue sections were tested by in situ polymerase chain reaction (IS-PCR) for the presence of BLV DNA using primers from the BLV gene (tax) responsible for malignant transformation. This gene is not related to any region within the human genome. Results for 211 subjects completed to date indicate that the breast tissue of women with a diagnosis of breast cancer tested positive for BLV DNA significantly more frequently (62%) than breast tissue from women with no history of breast cancer (23%) (P<= .0001; age-adjusted odds ratio = 5.4, confidence interval = 2.42-11.9). In 55% of pairs of malignant and “uninvolved” breast tissues from the same breast cancer patient, BLV was present in the nonmalignant breast epithelium. This suggests that virus infection may have preceded malignant transformation, i.e. cancer may have been a rare, delayed event within a population of BLV-infected cells widespread in the breast tissue (field effect), rather than virus infection being selective for cells already malignant. If further studies support our data, and indicate how the virus is transmitted to humans, it may be possible to prevent some breast cancer cases by preventing or controlling human infection with BLV. This work was supported by funds from the California Breast Cancer Research Program of the University of California, Grant 6PB-0075 and the U.S. Army Medical Research and Materiel Command, grant DAMD17-02-1-0320.
Humans have Antibodies Reactive with Bovine Leukemia Virus
Periodical:AIDS Research and Human Retroviruses
Index Medicus:
Authors: Buehring GC, Philpott SM, Choi KY
Yr: 2003 Vol: 19 Nbr: 12 Abs: Pg:1105-1113
Bovine leukemia virus in human breast tissue.
Periodical:Breast Cancer Research
Index Medicus: Breast Cancer Res
Authors: Choi KY, Jensen HM, Buehring GC
Yr: 0 Vol: 3 Nbr: Abs: Pg:S5