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. 2009 Dec 29;106(52):22393-8.
doi: 10.1073/pnas.0910753106. Epub 2009 Dec 11.

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

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

Gretchen L Hermes et al. Proc Natl Acad Sci U S A. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Effect of long-term social isolation on mammary tumor growth and diagnosis at 15 months. (A) Tumor burden (mean ± SEM) after living alone or in noncrowded social groups. (B) Rats with ductal carcinoma in situ (DCIS) or malignant tumors were primarily socially isolated; those with benign or no tumors lived in groups. (C–H) Wide range of naturally developing mammary tumors: (C) fibroadenoma; (D) lactating adenoma; (E) intraductal papilloma; (F) DCIS; (G) invasive ductal carcinoma; (H) fibrosarcoma.
Fig. 2.
Fig. 2.
Corticosterone dysregulation evident in young socially isolated females (3 months old) and severe by middle age (13 months old). (A) High corticosterone response and normal recovery (mean ± SEM) after an acute stressor, predator odor. (B) Low baseline corticosterone at the diurnal rhythm nadir. (C) A high prolonged corticosterone response, still rising from baseline 1 h poststressor, and delayed recovery 2 h post-stressor.
Fig. 3.
Fig. 3.
Glucocorticoid (GR), estrogen (ER), and progesterone (PR) receptor status (brown stain) in different mammary tumor types. (A) Fibroadenoma: GR+ in epithelial and stromal cells, ER+ and PR+ only in epithelial cells. DCIS: GR+, ER+ and PR+. Fibrosarcoma, GR+ and ER+, but PR−. (B) Isolation and the relative distribution of GR (+ = nucleus vs. − = cytoplasm). (C) Exemplars: grouped: more cytoplasmic GR (brown surround-blue center); isolates: more nuclear GR (brown center-blue surround).
Fig. 4.
Fig. 4.
Social isolation exacerbated three types of behavioral stress responses (age specific z-score mean ± SEM.) assessed in young adulthood (5 months) and repeated in middle age (15 months). Exploration Stress: Social Condition F(1,36) = 52.1, P ≤ 0.0001; Age F(1,36) = 1.8, NS; Interaction F(1,36) = 4.8, P ≤ 0.03 (Isolated animals did not improve with age as did those in groups.) Anxiety: Social Condition F(1,34) = 13.80, P ≤ 0.001; Age F(1,34) = 0.1, NS; Interaction F(1,34) = 0.0, NS. Boldness: Social Condition F(1,34) = 57.5, P ≤ 0.0001; Age F(1,34) = 0.0, NS; Interaction F(1,34) = 0.2, NS.
Fig. 5.
Fig. 5.
Experimental protocol of biobehavioral assays: ▴ Corticosterone stress responses; ■. Exploration stress responses: ● vigilance testing, ······· ovarian cyclicity, and – – – — tumor palpation.

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