Exposure to psychosocial stressors and ensuing stress physiology have been associated with spontaneous invasive mammary tumors in the Sprague-Dawley rat model of human breast cancer. Mammary gland (MG) development is a time when physiologic and environmental exposures influence breast cancer risk. However, the effect of psychosocial stress exposure on MG development remains unknown. Here, in the first comprehensive longitudinal study of MG development in nulliparous female rats (from puberty through young adulthood; 8–25 wks of age), we quantify the spatial gradient of differentiation within the MG of socially stressed (isolated) and control (grouped) rats. We then demonstrate that social isolation increased stress reactivity to everyday stressors, resulting in downregulation of glucocorticoid receptor (GR) expression in the MG epithelium. Surprisingly, given that chemical carcinogens increase MG cancer risk by preventing normal terminal end bud (TEB) differentiation, chronic isolation stress did not alter TEBs. Instead, isolation blunted MG growth and alveolobular differentiation and reduced epithelial cell proliferation in these structures. Social isolation also enhanced corpora luteal progesterone at all ages but reduced estrogenization only in early adulthood, a pattern that precludes modulated ovarian function as a sufficient mechanism for the effects of isolation on MG development. This longitudinal study of natural variation provides an integrated view of MG development and the importance of increased GR activation in nulliparous ductal growth and alveolobular differentiation. Thus, social isolation and its physiological sequelae disrupt MG growth and differentiation and suggest a contribution of stress exposure during puberty and young adulthood to the previously observed increase in invasive MG cancer observed in chronically socially-isolated adult Sprague-Dawley rats.
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We thank Drs. Terri Li and Gabrielle Baker for pathology expertise, and Dr. Paul Volden for sharing his expertise with the social isolation model. We are indebted to Mike McCarthy for Biopsychological Sciences Building operations crucial for this longitudinal research. This work was supported by National Institutes of Health (NIH) R01-CA148814 to SDC and MKM and The Institute for Mind and Biology, University of Chicago to MKM. Susan G. Komen GTDR16376189, Howard Hughes Medical Institute Med-into-Grad Scholars Program, NIH Grants T32-CA009594 and T32-DK087703 provided stipend support for MBJ. NIH P30-CA014599 supported The University of Chicago Comprehensive Cancer Center core facilities.
National Institutes of Health and University of Chicago Animal Care Guidelines were followed for the use of animals in all studies.
Conflict of Interest
The authors declare that they have no conflict of interest.
Electronic Supplementary Material
Supplemental Fig. 1 Mammary gland (MG) whole mounts. Representative digital images of right inguinal MG of rats aged 8, 13, 17, 21, and 25 weeks, after exposure to grouped or isolated social condition since weaning. Dashed line indicates perimeter of mammary ductal tree. Scale bars, 5 mm.
Supplemental Fig. 2 Color deconvolution for quantification of mammary gland (MG) structures. Ductal structures, stroma, and adipose tissue. A representative section of a left inguinal MG (H&E stain), hematoxylin stains ductal structures purple, eosin stains stroma and blood vessels pink, and unstained white adipose tissue.
Supplemental Fig. 3 Association between mammary gland stroma and ductal structures in grouped and isolated rats. Correlation between stroma and ductal structures observed on H&E slides at 17, 21, and 25 weeks of age; R = 0.70, *** P < 0.001, n = 26.
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Johnson, M.B., Hoffmann, J.N., You, H.M. et al. Psychosocial Stress Exposure Disrupts Mammary Gland Development. J Mammary Gland Biol Neoplasia 23, 59–73 (2018). https://doi.org/10.1007/s10911-018-9392-4
- Mammary gland
- Young adulthood
- Terminal end buds
- Alveolobular development