In cancer-ridden rats, loneliness can kill: Isolation and stress identified as contributing to breast cancer risk

The researchers found that isolation and stress result in a 3.3-fold increase in the risk of developing cancer among rats with naturally occurring mammary tumors.

The research establishes, for the first time, that isolation and stress could be a factor in human breast cancer risk, said Martha McClintock, a psychologist at the University of Chicago and an author of a paper in current issue of the Proceedings of the National Academy of Sciences. Researchers at the University have been studying social isolation in the context of breast cancer development after having found that that many women living in high-crime neighborhoods must deal with a variety of stressors, including social isolation. In particular, African American women have been noted to have an earlier onset of breast cancer, although total incidence is similar to women from other ancestries.

"We need to use these findings to identify potential targets for intervention to reduce cancer and other and its psychological and social risk factors," said McClintock, the David Lee Shillinglaw Distinguished Service Professor in Psychology and Comparative Human Development at the University. "In order to do that, we need to look at the problem from a variety of perspectives, including examining the sources of stress in neighborhoods as well as the biological aspects of cancer development."

The results of the study are published in a PNAS paper titled, "Social Isolation Dysregulates Endocrine and Behavioral Stress While Increasing Malignant Burden of Spontaneous Mammary Tumors." Gretchen Hermes, a former researcher at the University and now a resident in psychiatry at the Yale University School of Medicine, is lead author of the study.

The paper is part of a series of publications by University of Chicago researchers exploring the connection between social isolation and breast cancer biology, and part of an ongoing research program at Chicago where work is being done on cancer by researchers from a wide number of disciplines. That work was enabled by the University's Biopsychological Sciences Building, designed for such interdisciplinary research on behavior and biology and enhanced when the University received a $10 million grant from the National Institutes of Health to finance its Center for Interdisciplinary Health Disparities Research and is supported by the University of Chicago Cancer Research Center.

The study published in PNAS found that isolation led to a higher production of a stress hormone, corticosterone, among rats that were kept alone and subjected to the disturbances of colony life as well as stressful situations, such as the smell of a predator or being briefly constrained. Additionally, the isolated rats took longer to recover from a stressful situation than rats that lived together in small groups.

The study also suggests a causal relationship between social interaction and disease by showing that living alone first causes rats to have higher stress hormones, beginning in young adulthood, become fearful, anxious and vigilant and then prone to malignancy in late-middle age. The study further showed that the stress hormone receptor entered the nucleus of mammary tumor cells in isolated rats, where gene regulation occurs, something that happened less often in the cells of the non-isolated rats.

The researchers further found that rats living in isolation experienced a 135 percent increase in the number of tumors and a more than 8,000 percent increase in their size. The impact of isolation was much larger than the impact another environmental source of tumor formation -- the unlimited availability of high-energy food.

In natural situations, estrogen and progesterone produced from ovaries play a role in the majority of naturally occurring mammary and breast cancers tumors. In the rat study, tumors naturally developed in late middle age, while ovaries were no longer fully functioning, further suggesting the role of isolation and stress hormones in cancer development.

Joining McClintock and Hermes in preparing the PNAS paper were Bertha Delgado, researcher at Ben Gurion University, Israel; Maria Tretikova, Resident in Pathology at the University of Chicago Medical Center; Sonia Cavigelli, Assistant Professor of Biobehavioral Health at Penn State University; Thomas Krausz, Director of Anatomic Pathology at the University; and Suzanne Conzen, Associate Professor of Medicine at the University. The National Institute of Environmental Health Sciences/National Cancer Institute, the U.S. Department of Defense, and the State of Connecticut Department of Mental Health and Addictive Services supported the research.

The paper is part of a series published by McClintock and her colleagues using animal models to study the onset of cancer.

Rats provide an excellent model for studying human health. They are gregarious animals that are constantly interacting, with complex social relationships and shared care for their young. Additionally, isolation is a natural part of their social order, as a rat stands sentry at each colony and needs to be extremely vigilant to danger on behalf of the rest of the group.

A paper published by University researcher Jason Yee and colleagues showed that rats that developed reciprocal supportive relationships during stress, in which they both asked for help and gave assistance to others, were likely to live longer. That research was reported in "Reciprocal Affiliation Among Adolescent Rats During a Mild Group Stressor Predicts Mammary Tumors and Lifespan," in the journal Psychosomatic Medicine.

Hermes was lead researcher in a paper published in Developmental Psychobiology that isolation disrupts the development of puberty in rats by accelerating maturation of ovarian function while simultaneously delaying mammary tissue development. As a result, the rats are more likely to development mammary tumors. The work was in a paper, "Isolation and the Timing of Mammary Gland Development, Gonadarche and Ovarian Senescence: Implications for Mammary Tumor Burden."

In a paper in the American Journal of Physiology, Hermes and McClintock reported that isolation caused a more pronounced inflammatory disease response in females than in males. That work was published in the paper "Social isolation and the inflammatory response: Sex differences in the enduring effects of a stressor."

More recently, in a paper published in Cancer Prevention Research, Conzen and McClintock reported that social isolation of a genetic mouse model of human breast cancer resulted in larger mammary tumor growth. In a paper titled "A model of gene-environment interaction reveals altered mammary gland gene expression and increased tumor growth following social isolation," Conzen and McClintock showed that social isolation was associated with the increased expression of specific sets of genes involved in metabolism and inflammation.