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

Abstract

In a life span study, we examined how the social environment regulates naturally occurring tumor development and malignancy in genetically prone Sprague-Dawley rats. We randomly assigned this gregarious species to live either alone or in groups of five female rats. Mammary tumor burden among social isolates increased to 84 times that of age-matched controls, as did malignancy, specifically a 3.3 relative risk for ductal carcinoma in situ and invasive ductal carcinoma, the most common early breast cancers in women. Importantly, isolation did not extend ovarian function in late middle age; in fact, isolated animals were exposed to lower levels of estrogen and progesterone in the middle-age period of mammary tumor growth, with unchanged tumor estrogen and progesterone receptor status. Isolates, however, did develop significant dysregulation of corticosterone responses to everyday stressors manifest in young adulthood, months before tumor development, and persisting into old age. Among isolates, corticosterone response to an acute stressor was enhanced and recovery was markedly delayed, each associated with increased mammary tumor progression. In addition to being stressed and tumor prone, an array of behavioral measures demonstrated that socially isolated females possessed an anxious, fearful, and vigilant phenotype. Our model provides a framework for studying the interaction of social neglect with genetic risk to identify mechanisms whereby psychosocial stressors increase growth and malignancy of breast cancer.breast cancer ͉ glucocorticoids ͉ physiological stress ͉ psychological stress ͉ social behavior

Morphine Suppresses Tumor Angiogenesis through a HIF-1α/p38MAPK Pathway

“…During hypoxia, p38 MAPK is activated as an early response to hypoxia [33][34] and inhibition of p38 activity, through genetic 22 or pharmacological manipulation, 35 suppresses HIF-1␣ accumulation. Depending on the cell type, p38 activation is necessary for HIF-1␣ phosphorylation as it reduces the ability to bind VHL and thus prevent proteosomal degradation and promote HIF-1 stabilization.…”

Fragrant environment with α-pinene decreases tumor growth in mice

“…Social isolation (living alone instead of group breeding), a known stressful condition, was associated with a significant increase in the size of mammary tumors in rats (6). Similarly, social support is linked to improved health outcomes among cancer patients (4).…”

Neonatal Experiences Differentially Influence Mammary Gland Morphology, Estrogen Receptor α Protein Levels, and Carcinogenesis in BALB/c Mice

“…Some studies examining cancer etiology suggest that the external environment of the offspring, such as the mother's diet or psychosocial stressors, can alter the hormonal microenvironment of the developing mammary gland, which may influence mammary gland development and the risk of carcinogenesis (1)(2)(3). Relevant to the present study, neonatal experiences, especially challenging or stressful experiences, have been shown to cause long-term developmental changes in the brain, influencing behavioral (e.g., coping) and physiologic (e.g., hormonal) profiles of rodents, primates, and humans (4)(5)(6)(7).…”