Loneliness can be deadly. In humans, there is a statistical relationship between social interaction and mortality – the more isolated you are, the lower your chances of living a long life. Rats kept in social isolation their entire life die at a younger age than littermates who lived in groups closer to their natural social structure. But how exactly does isolation kill a rat? Under normal conditions, an infectious disease such as pneumonia is typically the cause of earlier mortality in a lonely rat. But when rats are kept in the sterile conditions of a laboratory animal facility, the cause of death is something quite surprising: breast cancer.
Those experiments – conducted by the group of Martha McClintock, professor of psychology at the University of Chicago – sparked a fruitful collaboration between McClintock and Suzanne Conzen, professor of medicine and a cancer expert. Last week, McClintock and Conzen gave a tag-team talk at the Chicago Breast Cancer SPORE seminar to present an overview of their research into the connection between social isolation, stress, and breast cancer, a line of study that could flip the current thinking about the disease. Traditionally, the psychological and social effects of breast cancer are considered to be the consequence of its diagnosis and treatment, but the research of these two laboratories suggests that these factors could be a cause as well, just as much as genetics or other biological sources.
“What I brought to the classic traditional approach is trying to flip it on its head,” McClintock said, “where you recognize that there are truly social forces which then change the psychological states of individuals in those interactions, and in turn their hormone function, cell receptors for those hormones, and then ultimately changes in gene expression.”
The link between the two labs was made over a hormone known for its role in stress responses, cortisol. McClintock observed that solitary rats behaved more anxiously than their group-housed peers, and found that they exhibit a larger and prolonged cortisol increase after a stressful event. Conzen’s laboratory was already studying the role of a receptor for cortisol, the glucocorticoid receptor (GR), in breast cancer, because women with the harder-to-treat “triple negative” form of the disease often show increased GR levels. Researchers in Conzen’s laboratory discovered that activating GRs can stimulate proliferation of breast cells and block the effects of chemotherapy drugs.
Could this be the missing biological step between isolation stress and breast cancer? At the lecture, Conzen tagged back to McClintock to talk about experiments on the tumors from her socially isolated rats. Unlike more common animal models of breast cancer where the tumor is instigated by a toxin or a genetic mutation, the naturally-occurring tumors in isolated rats show a similar diversity to that seen in human tumors. Some rats grow benign tumors, some malignant, and different tumors have the different hormone receptor profiles that are used for classification and treatment choices in patients – including, in some cases, glucocorticoid receptors.
“This to me was very exciting because in the rat model we have a good model of the diversity of breast pathology that happens [in humans] and it is increased by isolation,” McClintock said. “I was happy to see it in the more natural, spontaneously-occurring cancer model rather than something that was induced.”
But an induced-tumor mouse model used by Conzen’s laboratory also added intriguing information to this growing theory. These experiments used genetically identical, transgenic mice with a predisposition for breast cancer. But splitting these mice at a young age into group-housed or isolated conditions produced very different results, as the isolated mice grew both more tumors and larger tumors than the mice raised in a social environment. When the researchers looked at gene expression in the two groups of mice, they found large differences – again, in mice that shared the same DNA. The timing of the gene expression changes were also interesting, Conzen said, because they seemed to appear relatively early in life, before the cancer.
“This was fascinating,” Conzen said. “Because what this said was that most of the gene expression changes that were different were happening before the invasive component of the cancer arose.”
Taken together, the evidence appeared to support a strong relationship between isolation, stress, and breast cancer pathology, at least in rodents. But as the seminar’s moderator Olufunmilayo Olopade said during the question-and-answer session, “human beings are much more complicated.” Certainly, McClintock and Conzen said, the evidence suggests that an effective intervention for breast cancer should consider social and psychological factors as well as medical. Julian Solway even wondered provocatively from the audience whether one could take this evidence to make a case for gun control as a preventive treatment for breast cancer – removing the stressful and isolating conditions created by gun violence.
“Women are evolving, society is evolving, and the rates of the different types of breast cancer are changing,” Olopade said. “There are a lot of things that are changing about a woman’s environmental health and social environment…that’s why this is an interesting approach.”
Williams, J., Pang, D., Delgado, B., Kocherginsky, M., Tretiakova, M., Krausz, T., Pan, D., He, J., McClintock, M., & Conzen, S. (2009). A Model of Gene-Environment Interaction Reveals Altered Mammary Gland Gene Expression and Increased Tumor Growth following Social Isolation Cancer Prevention Research, 2 (10), 850-861 DOI: 10.1158/1940-6207.CAPR-08-0238
Hermes, G., Delgado, B., Tretiakova, M., Cavigelli, S., Krausz, T., Conzen, S., & McClintock, M. (2009). Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors Proceedings of the National Academy of Sciences, 106 (52), 22393-22398 DOI: 10.1073/pnas.0910753106