Stress and Risk of Breast Cancer: Is Therea Plausible Link?

Candyce H. Kroenke, ScD and Laura D. Kubzansky, PhD

Psychosocial factors have long been implicated in cancer eti-ology, and research in this area continues to be of interest.Although associations have frequently been observed, demon-strating that psychosocial factors are involved in cancer causa-tion has been difficult, in part because it is difficult to show re-lationships between exposures and disease outcomes that arenonproximal on the exposure–to–disease pathway with diseasesthat have long time-to-event horizons. Advancing this field ofresearch will require that links be demonstrated through inter-mediate outcomes, including cancer precursors and other surro-gate measures of cancer outcomes. Moreover, as emphasizedhere, it will be important for investigators interested in psy-chosocial research to look beyond simple exposure–disease re-lationships and think more in depth about the range of knownbiological mechanisms, how these mechanisms may influencethe direction of particular exposure–outcome relationships, andhow they are relevant in the causation of specific cancers.

An example considered here is research evaluating the pu-tative link between stress and breast cancer etiology. In theUnited States, almost 2 million women are alive after havingbeen diagnosed with breast cancer1 and more than 200,000 newcases are diagnosed each year.2 Stress is a common exposure,and a great deal of concern has been expressed that stress maycontribute to the development of breast cancer. Indeed, manywomen with breast cancer believe that stress or depression con-tributed to the development of their disease.

Stress is most often hypothesized to increase the risk ofbreast cancer though downregulation of the immune system.This hypothesis is based on a variety of research examininglinks between stress and immune function as well as relation-ships between immune function and general cancer risk. Actingvia the hypothalamic-pituitary-adrenal axis in a complex feed-back loop between the central nervous system and the immunesystem, stress is known to increase cortisol levels.3-5 Chronicstress can lead to frequent release of cortisol and persistentlyhigh cortisol levels,6 which in turn can lead to immune suppres-sion.7-13 Because the immune system is invoked in eliminatingmutated cells, reductions in immunity could theoretically leadto more rapid development of breast cancer.

Research has established reasonably convincingly thatchronic stress serves to compromise immune function.7,9,12,13

However, links between immune downregulation and breastcancer in human populations have not been demonstrated, andthis relationship would need to be established to provide con-vincing evidence of a positive association between stress andrisk of breast cancer via this mechanism.

Some limited data are available that may shed light on thisquestion. Patients with severely compromised immune systems,

such as those with acquired immunodeficiency syndrome(AIDS) or those receiving immunosuppressants, are at higherrisk of developing certain cancers, including Kaposi’s sarcoma,cervical carcinoma, non-Hodgkin’s lymphoma, or nonmel-anoma skin cancer. Although stress may well influence the de-velopment of cancer in organ systems with high cell turnover,cell turnover in the breast is much less rapid. Two studies ex-amining the risk of cancer among severely immunocompro-mised individuals found lower risks of breast cancer among pa-tients with AIDS (relative risk, 0.5; 95% confidence interval,0.3-0.8)14 and among women taking immunosuppressive drugsafter an organ transplant (relative risk, 0.75; P = 0.009).15

Although issues of competing risks may limit the relevance ofthese particular findings, they are informative nonetheless. Ifevidence fails to support such theorized biological mechanismsfor how stress might increase breast cancer risk, then it will beimportant to reconsider the nature of a relationship betweenstress and breast cancer or the mechanisms by which a relation-ship may occur.

Numerous studies have been conducted on the potential re-lationship between stress and breast cancer risk. Most havemeasured stress in terms of specific adverse life events (be-reavement, job loss, divorce, disasters, or family illness ordeath),16 and a few have examined chronic stress exposures.Epidemiologic research considering an association between ei-ther stressful life events or chronic stress and breast cancer hasproduced decidedly mixed results.

Previous studies have shown positive associations betweenadverse events and breast cancer risk, but many of these studieshave been retrospective, and the experience of having breastcancer may cause women to recall more stressful events thanthey would otherwise. In a meta-analysis of 29 studies judged tobe of good quality (all but 1 of which was retrospective),Petticrew and colleagues found that recent adverse life eventsdid not seem to be causative factors in the development ofbreast cancer.17 Although adverse events usually have not beenrelated to risk of breast cancer in prospective studies, a recentprospective study by Lillberg and colleagues found a positiveassociation between adverse life events and risk of breast can-cer,18 findings that need to be replicated. In that study, positivefindings were noted only for a particular subset of adverse lifeevents such as divorce or separation, death of a spouse, anddeath of a close relative. Other adverse events were found to beunrelated to breast cancer.18 A count of events that cause lifechange (even if such a count were to focus primarily on nega-tive life events) may not adequately capture the experience ofstress.19

Biologically, it is more plausible that daily chronic stres-sors, which can persist over long periods, should have a greaterinfluence on breast cancer in the long term. A couple of studieshave examined these links by looking at chronic stressors, buttheir findings have not provided support for the hypothesis of astress-breast cancer link. For example, in a prospective cohort

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study, our group found no increased risk of breast cancer asso-ciated with chronic stress from caregiving in the Nurses’ HealthStudy.20 Similarly, our group also found no increased risk ofbreast cancer associated with high-strain jobs as compared withlow-strain jobs (Abstract 3–41).

Given the lack of data that could be used to evaluate the hy-pothesis in a convincing way, researchers continue to believethere might be a link between stress and breast cancer. Studiesthat systematically examine possible mechanisms might help toevaluate this link more thoroughly. For example, to promote abetter understanding of the nature of the relationship betweenstress and breast cancer risk, investigators may wish to consid-er mechanisms other than alterations in immune function. Thereare other ways in which stress might be linked to breast cancer,and consideration of such linkages may lead to alternative hy-potheses. In fact, the empirical evidence available to date sug-gests that stress has little influence on breast cancer and mayeven reduce the risk of breast cancer.

Although stress may increase the risk of breast cancerthrough mechanisms such as DNA damage, faulty DNA repair,inhibition of apoptosis, effects on endocrine variables, or so-matic mutation,21 other behavioral and metabolic mechanismsexist by which stress might either increase or decrease the riskof breast cancer, and the effects may vary depending on whethera woman is premenopausal or postmenopausal. Stress may in-fluence breast cancer risk through effects on lifestyle factors(e.g., physical activity, smoking) and Syndrome X factors, in-cluding body mass index, central adiposity or insulin levels.Each of these pathways should be tested and evaluated for itsrole in any relationship between stress and breast cancer.

Further, although stress has been related to upregulation ofestrogen in animal studies, some evidence suggests that stressmay in fact reduce levels of endogenous sex steroid hormonesin humans, which would suggest a possible inverse relationshipbetween stress and risk of breast cancer. This pathway has re-ceived little attention but is particularly important given that thelevel of endogenous hormones is the predominant mechanismin the development of breast cancer.22-24 Some limited evidenceexists to suggest the plausibility of such a pathway. Recent stud-ies have found that chronic stressors and depression may sup-press estrogen levels and lead to early menopause25-27—factorsrelated to a lower risk of breast cancer. Although job strain wasnot related to estrogen levels in the Schernhammer study (seeAbstract 3–41), in our study of caregiving, which involved pre-dominantly postmenopausal women,20 women providing manyhours of caregiving had significantly lower levels of estradiol (P< 0.01) and bioavailable estradiol (P = 0.03) than women whoprovided10 caregiving, and those women reporting moderate orextreme stress from caregiving had a borderline lower risk ofbreast cancer (relative risk, 0.82; 95% confidence interval, 0.68-1.00) than women who provided no caregiving.

To the extent that immune downregulation has an adverse ef-fect on breast cancer outcomes, a corresponding decline in estro-gens may obscure evidence of this mechanistic pathway. Giventhe strength of the evidence that endogenous hormone levels in-fluence breast cancer risk, advancing our understanding of howstress might influence breast cancer will require critical examina-tion of the influence of stress, particularly chronic stress, on en-dogenous hormone levels.

Psychosocial researchers have conducted numerous studiesof stress and breast cancer, with some showing positive findingsand others showing null or even inverse findings. The best cur-rent evidence suggests that psychosocial factors do not have animportant role in breast cancer etiology. However, explorationof biological mechanisms by which stress might influencebreast cancer has been limited, and research is needed in thisarea. Future studies should take into account those mechanisticpathways that have been identified as being important in etio-logic research. At a minimum, it will be important to criticallyconsider various biological and behavioral mechanisms whendevising hypotheses. Such an approach will not only help toclarify the links between psychosocial factors and breast cancerbut will also lend credence to research on psychosocial factorsand chronic disease.

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