Isolation and the timing of mammary gland development, gonadarche, and ovarian senescence: Implications for mammary tumor burden

Abstract

In this study of Norway rats, we hypothesized that lifelong psychosocial experiences, social isolation or group living, trigger different developmental trajectories in the ovarian system, contributing to predisease pathways for spontaneous mammary tumors. Epidemiological studies indicate that early puberty and delayed menopause are risk factors for breast cancer. To that end, we took a cross-sectional, prospective approach and examined the ovarian system at two developmental points, young adulthood and middle age. We assessed ovarian function at both points, as well as mammary gland development at puberty and mammary tumor burden in middle age. Social isolation dissociated two components of puberty; it accelerated maturation of ovarian function while it simultaneously delayed mammary tissue development thereby increasing the exposure of developing breast parenchyma to high levels of estrogen. By mid-life, socially isolated rats had greater tumor burden despite having entered estropause prematurely, demonstrating that isolation did not increase tumorigenesis by prolonging ovarian function. These findings are discussed in the context of facultative lifespan strategies for rats born at different times of year and those living in isolation or in a large burrow community. ß 2008 Wiley Periodicals, Inc. Dev Psychobiol 50: 353-360, 2008.

Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors

“…In this rat model, however, social isolation was associated with senescent ovaries at the age of tumorigenesis and growth; few isolated rats had hormonally active follicles or corpora lutea, (23), confirmed here by the condition of their vaginal epithelia. Therefore, ovarian function at best plays a permissive role, and likely does not account for the larger and more malignant tumors in isolates.…”

“…First, it is a model of spontaneous tumors, which recapitulate most malignant and benign tumors in humans more accurately than the more expedient models using transgenes or carcinogens to stimulate rapid cancer growth or xenografts in which human cancer cells are injected into immunodeficient mice. Because this is a life span animal model of disease that examines dynamic interactions between the organism and its environment over a relatively long period, it illustrates not only the interaction between early stress responsiveness and later tumor pathology, but also tradeoffs between short-term benefits early in the life span, such as enhanced fertility of early ovarian maturity (23), yet increased disease burden at its end. Our data also point to the important and the somewhat unexpected role of the stress hormones in cancer biology.…”

“…5; pubertal data and methods are in ref. 23). In short, we randomly assigned 20 rats to socially isolated housing in a rack of single cages (26 ϫ 23 ϫ 22 cm) and 20 rats to four groups of five, each group in a large cage (46 ϫ 61 ϫ 36 cm).…”

“…In a series of bi-monthly health checks (Fig. 5), trained technicians palpated all mammary glands of middle-aged animals and noted the location and size of all nodules, using standard technique (23,40). Estimates of tumor weight by palpation predicted the dissected tumor weight.…”

“…Rapid growth could be mediated by up-regulation of genes involved in cell proliferation and/or cell survival, for example, SGK1, MKP1, Myc, and AKT. Some of these pathways are also regulated by ovarian steroids, although isolation accelerates reproductive senescence (22,23), suggesting that estrogen and progesterone receptor status might not be associated with tumor burden in middle-aged and socially isolated female rats.…”