by Maychai Brown
A year ago, I heard about the research being done by Quebec environmental toxicologist Dr. Pierre Ayotte on the relationship between breast cancer and the highly persistent compound p,pi-DDE, the main metabolite of the insecticide DDT*. (See BCAM Bulletin, DDT and Breast Cancer, Vol. 16, No. 2, Spring 2008.) I was intrigued because of two memories that have stayed with me over the years I've been involved with BCAM.
The first was a statement by keynote speaker, Dr. Annie Sasco, at the 3rd World Conference on Breast Cancer in 2002: "There is resistance in the scientific community to research on the environment." The second memory resulted from filmmaker Gerry Rogers's presentation at BCAM's 2002 Annual General Meeting where she revealed that several childhood friends who had accompanied her on their bikes in pursuit of the municipal Winnipeg DDT spray trucks—deliberately filling their lungs with the pleasant vapour—had shared the same outcome: breast cancer.
Apparently, Dr. Ayotte not only had embraced environmental research but was interested in the very substance Rogers had questioned. I caught up with him at his lab at the Institut national de sante publique du Quebec (INSPQ) in Ste. Foy in March. We had an extensive conversation not only about his work but also about the status of environmental research vis a vis breast cancer.
Research on p,pi-DDE
Dr. Ayotte describes himself as an "environmental toxicologist-epidemiologist." Although his PhD is in toxicology, he has collaborated for 15 years with epidemiologists "... to develop valid measures of exposures to toxicants for use in population studies." He recounted a series of experiments that unfold like a detective story.
The story starts in 1993 when he joined Dr. Eric Dewailly of the Public Health Research Unit (at the Centre hospitalier universitaire de Quebec) who had been working on a small pilot study on breast cancer and DDT in the Quebec City region. Ayotte and Dewailly noticed that the women who had estrogen receptor positive (ER+) breast cancer also had higher concentrations of p,pi-DDE in their blood as compared to women in the control group who were disease-free.
The next challenge was to replicate the results in a larger study; this started in 1995, again looking at women in the Quebec City region. This time they looked at other persistent organic pollutants such as PCBs and other organochlorine pesticides in addition to DDT. Their hypothesis was that the blood samples of the women who had breast cancer would show higher levels of p,pi-DDE and other organochlorines as compared to the control group. Dr. Ayotte explained,"We did not see an increased risk of cancer related to the levels of p,pi-DDE ... but what we saw was that, in the breast cancer cases with elevated levels of p,pi-DDE, the cancer was more aggressive than in breast cancer cases with low levels of the chemical. This led us to hypothesize that this compound was not causing breast cancer but was exacerbating the progression of the disease."
p,pi-DDE, an Anti-androgen
At this point, other researchers were noticing a curious characteristic of p,pi-DDE: it was a powerful antagonist of the male hormone testosterone, labelled an 'anti-androgen'.² This was significant in view of research that androgens exert control over the proliferation of mammary cells.³ Dewailly and Ayotte speculated that androgen antagonism might be related to their earlier observation of the relation between p,pi-DDE and the aggressiveness of breast cancer. Put simply, if androgens play a role in modulating breast cell division and if p,pi-DDE disables androgens, this could explain why p,pi-DDE is associated with aggressive breast cancers.
In 2003, they had the opportunity to test this hypothesis with funding from the Canadian Breast Cancer Research Alliance (CBCRA). In order to zero in on p,pi-DDE and other compounds that blocked the effect of androgens, they planned a series of in vitro experiments in which they would add several environmental anti-androgens to human breast cancer cell lines, using a particular breast cancer cell line, CAMA-1, that expresses two kinds of hormone receptors – androgen and estrogen.
They observed that cells proliferated when estrogen alone was added. However, when both estrogen and androgen were added, the cell proliferation decreased. As they expected, when estrogen, androgen and p,pi-DDE were added, proliferation increased. Additional work showed that the degree of cell proliferation was linked to the added concentration of p,pi-DDE, a further indication of a cause-and-effect relationship. Their research was published in the journal Breast Cancer Research (February 2008).
As Dr. Ayotte pointed out, this research is controversial due to conflicting evidence about androgen's role in tumour growth. There is evidence that androgens might themselves be considered a risk factor for breast cancer because they are susceptible to conversion into estrogen by the enzyme aromatase – with devastating results for women with ER+ (estrogen receptor positive) breast cancer. Noting that many environmental anti-androgens exist in addition to p,pi-DDE, Dr. Ayotte concluded, "Personally I think we should [give] closer scrutiny to these compounds that may act to block androgen receptors."
It appears there is more to learn about the complex interplay between androgens and different types of breast cancer cells, and also about how these mechanisms change when anti-androgens are present. The last chapter of this story has yet to be written.
Lifestyle vs. Environment
I asked Dr. Ayotte to predict how the effects of breast cancer might best be alleviated in the next ten years—through better treatment, lifestyle changes or by curbing environmental toxins. He said, "It's a good idea to put into perspective what we know. I think it's important to work on the environmental causes of breast cancer, but I don't think it's going to be as big as working on obesity and exercise ... The question is how much you think you can prevent and where should society allocate more effort." He cited the statement quoted recently in the joint report of the World Cancer Research Fund and the American Institute for Cancer Research that, in the U.S., breast cancer could be reduced by 38 percent through lifestyle changes.4 (See page 6 for another view.) Looking at all cancers, he feels that environmental factors (exposure to chemicals present in food, water, air and consumer products) are responsible for a much smaller percentage of cancers than are lifestyle factors.
BCAM would disagree with him over this assessment of the relative importance of lifestyle vs. the environment. Be that as it may, Dr. Ayotte thinks environmental causes are still responsible for a significant amount of cancers deserving the attention of researchers.
Environmental Research Now
One of my original interests in interviewing Dr. Ayotte was to find out his perspective on whether Dr. Sasco's pronouncement in 2002 still held true: In 2009, is there still resistance in the scientific community toward environmental research? What about Canada in particular?
Dr. Ayotte was confident: "It's ... possible to get funding to conduct research on environment and environmental health if your hypothesis is sound." As proof, he cited the current and continuing research on bisphenol-A. He also confirmed the strength of environmental research in Canada, reeling off names of researchers Canada-wide, including several with whom he collaborates closely: Dr. Jacques Brisson at Universite Laval whose interests include the effects of various nutritional compounds on breast density; Dr. Claire Infante-Rivard, a McGill epidemiologist studying pollutants in drinking water and gene/environment interaction; Dr. Kristan Aronson, epidemiologist at Queen's University studying the relation between polycyclic aromatic hydrocarbons (PAHs) and cancer. Outside his own areas of interest, he offered: epidemiologist Marie-Elise Parent at INRS-Institut Armand-Frappier whose interests include possible links between cell phone use and cancer; Dr. Jacques Siemiatycki at Universite de Montreal working on workplace exposures and cancer, and Dr. John Spinelli, a statistician at U.B.C., who is exploring environmental risk factors for breast cancer including PAHs and light at night.
Environmental Research – The Future
Having recently returned from the annual meeting of the Society of Toxicology in Baltimore, Dr. Ayotte reported that nanotechnology has become the hot topic for researchers. Interest in research on PCBs and DDT has faded somewhat, probably because of the amount of research done from 1993 to the present. He also became aware of growing anxiety among U.S. researchers about the security of their funding. Dr. Ayotte thinks that the threat is not as great in Canada due to the relative strength of the economy.
Still, the amount of research on breast cancer that takes place in the United States and in other countries is bound to be affected by the current economic turmoil. The world may have to wait a long time before it gets definitive answers on the causes of breast cancer. In these uncertain times it is worthwhile to remember something else Annie Sasco said in 2002, "The research will happen only if women push, push, push for it."
Other Environmental Anti-androgens
Fungicides: vinclozolin, procymidone and prochloraz
Flame retardants: polybrominated diphenyl ethers (PBDEs)
Plasticizers: phthalate esters, ex.: diethyl hexyl phthalate (DEHP)
*Although registration of DDT in Canada was discontinued after 1985 and existing stocks were disposed of by 1991, it is still used in some parts of the world and can be transported long distances through the atmosphere.¹
- Environment Canada website: http://www.ec.gc.ca/nopp/docs/consult/toxicReg/ddt/en/fact.cfm
- Kelce WR, Stone CR, Laws SC, Gray LE, Kemppainen JA, Wilson EM. Persistent DDT Metabolite p,p1-DDE is a potent androgen receptor antagonist, Nature 1995, 375:581-585.
- Dimetrikakis C, Zhou J, Wang J, Belanger A, LaBrie F, Cheng C, Powell D, Bondy C: A physiologic role for testosterone in limiting estrogenic stimulation of the breast, Menopause 2003, 10:292-298
- Prevention the 'Cure' for Cancer: Study. The Montreal Gazette, Feb. 27, 2009