Linked by bovine leukemia virus antibodies
BERKELEY, California––A University of California at Berkeley cancer research team on September 15, 2015 released data tentatively linking the ubiquitous presence of bovine leukemia virus (BLV) among U.S. dairy and beef cattle herds to the incidence of breast cancer in women.
The findings, published in the peer-reviewed online scientific journal PLOS ONE, were amplified on September 17, 2015 by ProMED-mail, the also peer-reviewed electronic information exchange maintained by the Program for Monitoring Emerging Diseases, reaching more than 60,000 human and animal health professionals worldwide.
May hit dairy as hard as health findings hit PMU
The U.S. Berkeley findings establish a statistical association, rather than proving direct cause-and-effect. But even the discovery of a strong association could potentially hit the $102-billion-per-year U.S. dairy industry as hard as the discovery of similar associations in 2002 and 2008 hit the then-$2-billion-a-year market for estrogen supplements made from PMU, short for pregnant mare’s urine.
The market for PMU drugs, including Premarin and PremPro, dropped abruptly to about $1 billion per year, and has remained in that range. The PMU drug sales crash approximately halved the numbers of mares used in PMU production, mostly in Canada, and the numbers of foals birthed to keep the mares producing PMU. While some of the fillies are used to replace older mares in the PMU barns, the majority of the foals are sold to slaughter.
The U.S. dairy herd included about 9.2 million cows at the end of 2014, according to U.S. Department of Agriculture data. Each cow in milk production births an average of one calf per year. About two million female calves per year replace older cows in milking herds. The male calves and the remainder of the females are raised for beef or veal.
“The association between BLV infection and breast cancer was surprising,” said lead study author Gertrude Buehring, who is a professor of virology in the Division of Infectious Diseases and Vaccinology at the U.C. Berkeley School of Public Health.
“It is important to note that our results do not prove that the virus causes cancer,” Buehring added. “However, this is the most important first step. We still need to confirm that the infection with the virus” found in many human women “happened before, not after, breast cancer developed, and if so, how.”
A retrovirus, meaning that it embeds itself and reproduces in the DNA of the infected host, BLV infects cattle blood cells and mammary tissue. Easily transmitted among cattle, mostly through infected milk and placental blood, BLV only emerges as a diagnosed disease in somewhat under 5% of infected bovines, but since practically all cattle on U.S. farms are slaughtered before reaching the equivalent of human middle age, far more might develop bovine leukemia if allowed to live longer.
Milk from 100% of large dairies has BLV antibodies
Noted Buehring et al in a statement describing their findings, “A 2007 USDA survey of bulk milk tanks found that 100% of dairy operations with large herds of 500 or more cows tested positive for BLV antibodies. This may not be surprising, since milk from one infected cow is mixed in with others. Even dairy operations with small herds of fewer than 100 cows tested positive for BLV 83% of the time.
Buehring et al in a 2014 study published in the peer-reviewed journal Emerging Infectious Diseases demonstrated that BLV can be transmitted to humans, contrary to longstanding previous medical belief.
“Studies done in the 1970s failed to detect evidence of human infection with BLV,” Buehring said. “The tests we have now are more sensitive, but it was still hard to overturn the established dogma that BLV was not transmissible to humans. As a result, there has been little incentive for the cattle industry to set up procedures to contain the spread of the virus.
BLV triples odds of having breast cancer
“The new paper,” the researchers explained, “takes the earlier findings a step further by showing a higher likelihood of the presence of BLV in breast cancer tissue. When the data were analyzed statistically, the odds of having breast cancer if BLV were present were 3.1 times greater than if BLV was absent.”
Pointed out Buehring, “This odds ratio is higher than any of the frequently publicized risk factors for breast cancer, such as obesity, alcohol consumption and use of post-menopausal hormones,” namely PMU-based estrogen supplements.
“There is precedence for viral origins of cancer,” the U.C. Berkeley researchers noted. “Hepatitis B virus is known to cause liver cancer, and the human papillomavirus can lead to cervical and anal cancers. Notably, vaccines have been developed for both those viruses and are routinely used to prevent the cancers associated with them.”
Could shift focus to prevention
Said Buehring, “If BLV were proven to be a cause of breast cancer, it could change the way we currently look at breast cancer control. This could shift the emphasis to prevention of breast cancer,” including by avoiding risk of exposure to BLV, “rather than trying to cure or control it after it has already occurred.”
(The full citation for the paper by Buehring et al is: Buehring GC, Shen HM, Jensen HM, Jin DL, Hudes M, Block G: Exposure to bovine leukemia virus is associated with breast cancer: a case-control study. PLoS ONE 10(9): e0134304.doi:10.1371/journal.pone.0134304. The study may be downloaded at <http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134304>.)
What the paper itself says
Explains the paper Exposure to bovine leukemia virus is associated with breast cancer itself, “Age, reproductive history, hormones, genetics, and lifestyle are known risk factors for breast cancer, but the agents that initiate cellular changes from normal to malignant are not understood. We previously detected BLV in the breast epithelium of humans. The objective of this study was to determine whether the presence of BLV DNA in human mammary epithelium is associated with breast cancer.
“The frequency of BLV DNA in mammary epithelium from women with breast cancer (59%) was significantly higher than in normal controls (29%).
“In women with premalignant breast changes the frequency of BLV DNA was intermediate (38%) between that of women with breast cancer and normal controls.”
Only genetics, radiation, & age are higher known risk factors
Under “Conclusions,” Buehring et al wrote, “The odds ratio magnitude was exceeded only by risk factors related to genetics (familial breast cancer), high dose ionizing radiation, and age.”
Explained the researchers, “Longstanding interest in viral initiation of breast cancer stems from the mouse model, the only animal breast cancer with a known etiology. Its causative agent, mouse mammary tumor virus, is a retrovirus,” like BLV, “transmitted from mother to pups via milk. Over the past 50 years there has been considerable interest in determining whether the mouse mammary tumor virus or a closely related human virus might be transmitted via milk and play an important causative role in human breast cancer. Numerous investigations (1970–1985) found no convincing evidence of a mouse mammary tumor virus-like virus in human milk or breast tissues,” but “more recent investigations have been divergent and no consensus has been reached.”
Observing that, “Most humans in Western cultures consume more cow’s milk products in a lifetime than they do human milk,” Buehring et al were motivated, they wrote, “to investigate whether a bovine virus might be an initiating agent for breast cancer. The most prevalent oncogenic virus of cattle is bovine leukemia virus.
Raw milk may be “missing link”
“Approximately 38% of beef herds, 84% of dairy herds, and 100% of large-scale dairy operation herds in the USA are infected with BLV,” but milk and meat from infected cattle is excluded from reaching consumers only if they develop diagnosed clinical leukosis.
“BLV-infected lymphocytes circulate through the blood of infected cattle. BLV also infects the mammary epithelial cells of cows and infected cells may be found in cow’s milk,” Buehring et al continued, “although pasteurization renders BLV noninfectious.”
Most milk products sold in the U.S. are made from pasteurized milk, but there is a sizeable and growing, albeit largely undocumented, market for raw milk, typically sold directly from farms to consumers.
African-Americans: less exposure, less risk
About 75% of African-Americans are lactose-intolerant, according to the Johns Hopkins Medical Health Library, and therefore tend to consume significantly fewer milk products than Caucasian-Americans. Not surprisingly, Buehring et al found that “Women of African ancestry had an overall frequency of breast tissue BLV of 29%, significantly lower than the BLV frequency in women of Caucasian ancestry (50%).”
Explained Buehring et al later in Exposure to bovine leukemia virus is associated with breast cancer, “A comparison of different racial/ancestry groups was not part of our original experimental design, but the conspicuously lower frequency of BLV DNA and breast cancer odds ratio in women of African versus Caucasian ancestry is worth mentioning and is consistent with the lower breast cancer incidence among African Americans after age 40, even though their mortality is higher. The number of African American subjects in this study however, was limited and further research is necessary to substantiate these observations.”
37% of breast cancer cases
Projected Buehring et al, “As many as 37% of breast cancer cases may be attributable to BLV exposure.”
However, Buehring et al cautioned, “How humans become infected with BLV is not known. Transmission from cattle to humans is plausible, as BLV is widespread in both beef herds and dairy herds. Although pasteurization renders the virus non-infectious and presumably thorough cooking of beef also does, many people have drunk raw milk and/or eaten raw or undercooked beef at some point in their life. Breast cancer incidence is markedly higher in countries with high milk consumption. Numerous prospective studies on dairy consumption in various defined populations, however, including one study that carefully evaluated unpasteurized milk consumption, found no significant relationship between cow’s milk consumption and breast cancer incidence.
“Human to human transmission is also plausible,” wrote Buehring et al. “Milk-borne transmission of BLV from cow to calf occurs naturally and HTLV, the human virus closely related to BLV, is transmitted primarily from nursing mother to child in endemic areas. Epidemiologic studies on human breast milk consumption, however, have not found a significant increase in breast cancer among women who were ever breast-fed as infants, compared with those who were never breast fed.”
Noted Buehring et al, “One potential challenge confronting the elucidation of BLV’s route of transmission to humans is the long agricultural association of humans with cattle, which began over 2,000 years ago [actually more than 5,000 years ago], while milk pasteurization in western countries was not standard practice until around 1925. This would have allowed ample time for BLV to enter the human population and become established, yet still be re-entering the human population under certain circumstances. The current reservoir for transmission to humans could, therefore, be cattle, humans, or both.”
“Validation is essential”
Buehring et al recommended several avenues for further study. “Validation by other investigators is essential,” Buehring et al acknowledged, “and a prospective study showing that viral infection preceded detectable cancer development would be desirable to support the idea of a causal association of BLV with breast cancer.
“Regardless of causality or of how the virus has been acquired by humans,” Buehring et al concluded, “if BLV were substantiated as a risk factor for breast cancer, its detection in breast fluid cells or tissues might serve as a biomarker to identify women at higher risk for developing breast cancer and perhaps warranting closer monitoring leading to early detection and treatment. Also, since BLV is a retrovirus, the opportunity presents itself to explore the effectiveness of anti-retroviral therapy in limiting or eliminating BLV before breast cancer could be initiated.”
Dairy products also linked by 2013 Kaiser study
Exposure to bovine leukemia virus is associated with breast cancer: a case-control study was published just over two and a half years after possibly related findings from a study funded by the National Cancer Institute of the National Institutes of Health appeared in the April 30, 2013 edition of the Journal of the National Cancer Institute.
The study, High- and Low-Fat Dairy Intake, Recurrence, and Mortality After Breast Cancer Diagnosis, was produced by a five-member team from the Kaiser Permanente hospital and health insurance company’s Division of Research, led by Candyce H. Kroenke.
Dairy fat is “source of estrogenic hormones”
Opened Kroenke et al, “Dietary fat in dairy is a source of estrogenic hormones and may be related to worse breast cancer survival. We evaluated associations between high- and low-fat dairy intake, recurrence, and mortality after breast cancer diagnosis.”
The study included data from 1,893 women who were “diagnosed with early-stage invasive breast cancer from 1997 to 2000,” and “completed the Fred Hutchinson Cancer Research Center Food Frequency Questionnaire after diagnosis.” Among the women were 1,571 from northern California, 227 from Utah, and 95 from other regions.
“A total of 349 women had a recurrence and 372 died during a median follow-up of 11.8 years, with 189 deaths from breast cancer,” Kroenke et al reported.
“High-fat dairy intake positively associated”
“Overall dairy intake was unrelated to breast cancer–specific outcomes, although it was positively related to overall mortality,” Kroenke et al found. “Low-fat dairy intake was unrelated to recurrence or survival. However, high-fat dairy intake was positively associated with outcomes. The higher risk appeared consistent across different types of high-fat dairy products.”
Summarized Kroenke to Science News, “Specifically, women consuming one or more servings per day of high-fat dairy had a 64% higher risk of dying from any cause and a 49% increased risk of dying from their breast cancer during the follow-up period.”
Categorized as “high-fat dairy products” for the purposes of the study were cream, whole milk, condensed or evaporated milk, milk-based puddings, ice cream, custard, flan, and cheeses and yogurts that were not specifically identified as “low-fat” or “non-fat.”
Health findings & PMU
The PMU industry has twice been hard-hit by publication of new findings from the U.S. government-funded Women’s Health Initiative linking estrogen supplements to health issues.
The most marked impact came after Women’s Health Initiative data in December 2008 associated the use estrogen supplements with an elevated death rate from breast cancer and an increased risk of developing kidney stones.
The 2008 findings came a little over seven years after the Women’s Health Initiative in July 2002 reported that estrogen supplements appear to be linked to a greater risk of women suffering from invasive breast cancer, heart attacks, strokes, and blood clots in their lungs.
Breast cancer warning
Based on the 2002 Women’s Health Initiative study results, the U.S. Food & Drug Administration in February 2003 began requiring all estrogen product labels to carry warnings that the products “may slightly increase the risk of heart attack, stroke, breast cancer, and blood clots.”
The FDA and most leading medical organizations believe these risks pertain to estrogens from all sources, not just PMU, but since the PMU-based products Primarin and Prempro had by far the largest estrogen supplement market share, their sales decline was steepest.
Premarin & Prempro
The Women’s Health Initiative breast cancer study looked at women who took the PMU-based estrogen drug Premarin in combination with progestin, the formula sold as Prempro.
“Women taking estrogen plus progestin are at greater risk from dying from the two leading causes of cancer death in women,” concluded study team leader Rowan T. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. Among the 15,387 women who participated in the second phase of the Women’s Health Initiative, the death rate from breast cancer among those who did not take estrogen plus progestin was 3.4 per 10,000; the rate among those who did was 5.3, or 40% higher––a rate of increased risk closely comparable to the 37% rate of increased risk projected by Buehring et al in Exposure to bovine leukemia virus is associated with breast cancer: a case-control study.
Estrogen supplements & kidney stones
Confirmation of the elevated risk of death from breast cancer associated with taking estrogen supplements came two weeks after the October 11, 2010 edition of Archives of Internal Medicine reported the link to risk of developing kidney stones. “Among more than 24,000 postmenopausal women taking either hormones or dummy pills, those using hormones were 21% more likely to develop kidney stones over about five years,” summarized Associated Press medical writer Lindsay Tanner.
“Those results suggest that over a year’s time,” assessed Tanner, “among 10,000 postmenopausal women taking hormones, five would develop kidney stones who wouldn’t have if they hadn’t used the pills. The risks were similar for women taking either Prempro, containing estrogen plus progestin, or Premarin, which contains only estrogen.”
Estrogen supplements & breast cancer fell together
After publication of the 2002 Women’s Health Initiative findings, the volume of prescriptions filled for PMU-based drugs reportedly fell from more than 110 million to about 40 million.
Along with falling hormone use since 2002, “Breast cancer diagnoses started to drop,” summarized Washington Post medical writer Rob Stein after the 2008 Women’s Health Initiative findings were published. “That appeared to help explain one of the biggest mysteries about breast cancer––why the number of cases rose steadily for decades. Hormone use probably played a key role, the study results suggest,” Stein wrote, “along with better detection by mammography and other factors.”
Early humane concerns
PMU was the active ingredient of the earliest birth control pills for humans, first marketed in Canada in 1941. The humane community voiced two major concerns about the PMU industry from inception.
One was that it involves keeping pregnant mares artificially closely confined, to collect their urine. The other was that impregnating the mares year after year to collect their urine creates a perpetual surplus of foals, for whom even then, when horses were still often used in farm work, there was little market demand except for slaughter.
The National Humane Review, published by the American Humane Association, issued an investigative report about the PMU industry in June 1947.