Psychosocially influenced cancer: diverse early-life stress experiences and links to breast cancer

Abstract

This perspective on Boyd et al. (beginning on page 1398 in this issue of the journal) discusses recent published research examining the interplay between social stress and breast cancer. Cross-disciplinary studies using genetically defined mouse models and established neonatal and peripubertal paradigms of social stress are illuminating biological programming by diverse early-life experiences for the risk of breast cancer. Understanding the mechanisms underlying this programming can lead to the identification of risk factors and sensitive developmental windows, enabling improved prevention and treatment strategies for this devastating disease.

Fig. 1

Conceptual model of diverse early-life stress experiences and their complex effects on risk of breast cancer. During the neonatal period, both brief (15 minutes) and long (4 hours) daily maternal separations resulted in increased mammary ductal complexity in adulthood compared with mice receiving normal maternal care, presumably as a result of heightened activity/responsiveness of the HPG axis (see adult ductal-morphology diagrams at the bottom of the figure; dark shading indicates stressed females). Neonatal rodents are relatively hyporesponsive to stress. Brief daily maternal separation and consequent attenuation of the HPA axis led to an interesting decrease in mammary cancer. The severe neonatal stressor of long daily maternal separation, however, overrides this hyporesponsiveness and leads to hypersensitivity of the HPA axis and increased mammary-cancer development in adulthood (11). The impact of stress during the peripubertal period, when rodents are hyper-responsive to stress, on breast-cancer incidence or progression is more complex. One study found that chronic stress induced by social isolation during the peripubertal period led to decreased mammary ductal complexity reflecting reduced activity/responsiveness of the HPG axis, which correlated with decreased carcinomas in an estrogen-sensitive model of mammary cancer (10). In a more-aggressive, less-estrogen–sensitive cancer model (marked with an asterisk), similar social isolation during the peripubertal period increased mammary tumor burden (9). As discussed in the text, the differential impact of peripubertal stress on HPA versus HPG programming may also underlie some of these discrepancies. Mammary glands in both of these peripubertal studies displayed similar changes in mRNA for regulators of key metabolic pathways, demonstrating significant effects of chronic stress initiated at this phase of development. The different impact on mammary cancer, however, suggests that the inhibitory effect of heightened stress on the HPG axis can override the deleterious effect (tumor progression) for some cancer types (discussed in the text). Note that mammary morphology in the normally treated control females differed somewhat between the studies reported in refs. 9 and . Although the basis for this difference is not clear (cross-fostering of pups, strain background, different ages and/or husbandry of mice, or a combination thereof), both studies show that the social environment during the neonatal or peripubertal period can strikingly alter mammary development that may alter breast-cancer risk. The inset diagram (middle) illustrates the well-documented pathway by which social or environmental cues can impact gonadal (HPG axis) or adrenal (HPA axis) steroid hormone secretions that provide signals to the brain and peripheral targets including the mammary gland. These studies indicate the importance of the timing of the stressor for mammary morphogenesis, and the consequences for tumorigenesis. Further research is needed to determine the effects of stressors and their timing on different breast-cancer subtypes, the consequences of individual variations in temperament in regard to stressor and stressor-timing effects, and the underlying mediators of psychosocial-stress effects in the mammary gland.