The Problem With Using Animals to Study Breast Cancer
The vast majority of animals used to study breast cancer are rats and mice. Mice, however, do not naturally develop mammary tumors, which means that rodents are poor models for breast cancer.2 Additionally, differences in the rates at which rodents and humans metabolize, absorb, and eliminate various compounds make rodents poor models for chemopreventative and chemotherapeutic research.3
In his review of the use of animals in breast cancer research, Georgetown University physiologist Robert Clarke criticizes animal researchers for using sloppy models that have little validity. He writes, “Despite the care investigators take in framing their hypotheses, many fail to take comparable care in the design and analysis of their in vivo studies.” Clarke’s review goes on to reveal a shocking aspect of breast cancer research using animals—animal data is inconsistent and cannot be reproduced by different investigators using the exact same protocols. Clarke writes, “[I]t is apparent that there are often differences in tumor incidence, multiplicity, and latency both within and among different laboratories.”4 It is a basic tenet of science that a model must be reproducible to be considered valid—this is clearly not the case with cancer experiments using animals.
In Breast Cancer Research, Jong Kim, Michael O’Hare, and Robert Stein sum up the situation bluntly: “[T]he most widely used animal models have a limited role in cancer research because the biology of rodents and their tumours differs significantly from that of humans and human cancer. The differences in developmental programmes of mouse and humans manifest in many ways, with size being an obvious example.”5 The researchers mention a number of crucial differences between cancer in rodents and cancer in humans, including the following:
- “The shorter lifespan of rodents means that observable tumours must have a rapid programme of progression, as mice can develop very malignant tumours showing multiple genetic alterations within a relatively short time period (6-18 months).”6 In contrast, it can take up to 30 years for cancerous human cells to form a malignant breast cancer.
- “Another difference lies in immortalization, which is a key step in tumour progression, and the ease with which rodent cells become immortalized.”7 “Immortalization” is a main mechanism of cancer growth in which cells do not self-destruct when they naturally should, leading to uncontrolled cellular growth.
- “Mouse and primary human cells have major differences in telomere dynamics and telomerase regulation.”8 Telomeres are the ends of DNA strands, which play a key role in cell division and DNA mutation—a major cause of cancer.
- “[T]he detailed morphology of most mouse tumours do not resemble the common human breast cancers and cannot be classified in an equivalent manner to the standard human tumour pathology grades and types. Rat tumours are likewise distinct and differ from both mouse and human counterparts in detailed histology. The metastatic patterns between the species are also different.”9
- “Breast cancer in humans usually spreads lymphatically, starting with local lymph glands, followed by distant metastasis predominantly to the bone, the brain, the adrenal gland, the liver and the lung. In contrast, mouse mammary cancers metastasize almost exclusively to the lung via the haematogeneous route.”10
- “Small animals, such as mice and rats, consume greater amounts of oxygen on a per-cell basis than larger animals. This will result in very different cellular microenvironments, particularly in relatively avascular and hypoxic tumors, where hypoxia-induced genes may play an important role in growth and differentiation.”11
Chemically Induced Cancers
Because mice and rats do not naturally get breast cancer, researchers have had to invent ways to cause mammary tumors to develop in them. The classic method is to chemically induce tumors using one of two chemicals—methylnitrosourea (MNU) or 7,12-dimethylbenz(a)anthracene (DMBA). Researchers then count the number of tumors that develop in groups undergoing different treatments.
Pharmacologist Stephen Barnes of the University of Alabama points out how ridiculous these chemical models are, writing: “[T]he existing models of breast cancer are limited in their usefulness because the mammary tumors induced by MNU and DMBA are not invasive. Tumor metastasis and angiogenesis are important aspects of human breast cancer.”14 In other words, because the tumors induced in animals through chemical exposure are not invasive, they cannot be models for invasive human breast cancer.
Dr. Leena Hilakivi-Clarke of Georgetown University’s Lombardi Cancer Center adds that “[c]hemically-induced mammary tumors in rodents are totally prolactin-dependent, at least during the stages of tumor progression, though the role of prolactin in human breast cancer is still unclear.”15 In contrast, human breast cancer is overwhelmingly dependent on a different hormone: estrogen. Clearly, if tumors induced in rodents and tumors that develop in humans are dependent upon different hormones for their growth, then they will not respond in the same way to either carcinogens or treatments.
Animal researchers often talk about the importance of validating observations. Robert Clarke, however, writes, “The validity of extrapolating the chemoprotective activity of a compound to the human disease, based on its ability to alter the pharmacokinetics of an experimental mammary carcinogen such as DMBA, remains unclear ….”16 After decades of use, these chemical models have never been properly validated, and because of their poor track record, researchers are increasingly abandoning chemically induced tumor models.
The use of chemically induced tumors has been disastrous for scientific progress. It is fair to say that the “war on cancer”—declared by the Nixon administration more than 30 years ago—has been greatly undermined by a reliance on studying chemically induced rodent cancers.
Xenograft Cancers
One of the more bizarre yet common ways that animals have been used in cancer research is as hosts for xenografts of human cancers. Researchers have been unable to produce human-like cancers in animals and have resorted to surgically implanting actual human cancers in rodents. However, as Kim et al. note, “Human breast cancer is one of the more difficult tumours to transplant directly into experimental animals,” and the procedure has a pitiful success rate—as low as 7 percent.17 Moreover, to obtain even these poor results, the animal’s immune system must be compromised. Dr. Kay-Uwe Wagner explains the fatal flaw in using immunosuppression, stating, “The lack of a normal immune response is a common weakness for using xenograft models in preclinical trials since a number of cancer therapies rely directly or indirectly on an intact immune system.”18
Even if a human tumor is “successfully” implanted in an animal, the result is far from a realistic model of human cancer. As Kim et al. note, the stroma problem is particularly insurmountable for xenografts: “Overall, xenografts contain fewer stromal cells and the stroma that does exist is murine in origin, resulting in a chimeric tumour. The biology of chimeric rodent/human tumours can differ significantly from that of humans and can result in unpredictable growth, differentiation or metastatic properties.”19
Wagner also points out that a human cancer won’t act like a human cancer if it is not bathed in human hormones. Regarding the xenograft model, Wagner writes: “[I]t does not reflect species-related incompatibilities of systemic factors produced by the host with the corresponding receptors of the graft. The implementation of this condition in the model design requires the expression of human hormones at near-physiological levels in the immunocompromised host.”20 Wagner goes on to explain that a xenograft model that uses human hormones is simply not feasible.
Transgenic Animals
Genetically engineered mice (GEM) and other transgenic animals have had their DNA altered by researchers in the hopes of turning them into “living models.” Despite the boastful claims of animal researchers, transgenic animals have been a huge disappointment.
One of the major problems with using genetically modified animals—a problem that is rarely acknowledged or discussed by researchers—is that these deformed animals die at an incredibly high rate. During a People for the Ethical Treatment of Animals (PETA) undercover investigation at the University of North Carolina’s animal care facility, a PETA investigator taped a conversation in which an animal care technician admitted that his staff simply could not keep transgenic rodents alive. Furthermore, transgenic animals who do survive are inevitably sick and suffer from immunodeficiency. Such animals cannot offer consistent or applicable answers to questions about what causes cancer and what can be done to treat and prevent it. It’s the industry’s dirty little secret.
When animals live long enough to be used in experiments, the test results are underwhelming because the tumors produced in transgenic rodents are different from human breast tumors. Wagner writes: “Approximately 50% of all human breast cancers are [estrogen responsive]-positive, but the vast majority of mammary lesions in GEM are ER-negative. Most GEM thus do not precisely recapitulate steroid receptor signaling during neoplastic transformation.”21 This flaw in transgenic models is likely fatal because most preventive and therapeutic approaches to breast cancer are estrogen-dependent.
Kim et al. note that the use of transgenic animals sometimes offers misleading data. For example, in genetically altered rodents, there is “enhanced tumourigenesis caused by pregnancy, whereas pregnancy is protective in humans.” 22
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2. Kay-Uwe Wagner, “Models of Breast Cancer: Quo Vadis, Animal Modeling?” Breast Cancer Research 6 (2004): 31-8.
3. Robert Clarke, “Animal Models of Breast Cancer: Experimental Design and Their Use in Nutrition and Psychosocial Research,” Breast Cancer Research and Treatment 46 (1997): 117-33.
4. Clarke 127.
5. Jong B. Kim et al., “Models of Breast Cancer: Is Merging Human and Animal Models the Future?” Breast Cancer Research 6 (2004): 22-30.
6. Kim et al. 22-3.
7. Kim et al. 23.
8. Kim et al. 23.
9. Kim et al. 23.
10. Kim et al. 23.
11. Kim et al. 23.
12. Wagner 35.
13. Jong B. Kim et al., “Three-Dimensional In Vitro Tissue Culture Models of Breast Cancer—a Review,” Breast Cancer Research and Treatment 149 (2004): 1-11.
14. Stephen Barnes, “The Chemopreventive Properties of Soy Isoflavonoids in Animal Models of Breast Cancer,” Breast Cancer Research and Treatment 46 (1997): 169-79.
15. Leena Hilakive-Clarke, “Estrogen-Regulated Nonreproductive Behaviors and Breast Cancer Risk: Animal Models and Human Studies,” Breast Cancer Research and Treatment 46 (1997): 143-59.
16. Clarke 126.
17. Kim et al., “Models.” 24.
18. Wagner 36.
19. Kim et al., “Models.” 27.
20. Wagner 36.
21. Wagner 32.
22. Kim et al., “Models.” 24.
