Psychosocial stress suppresses tumor progression in a murine model of spontaneous, metastatic breast cancer

Abstract

Late-stage breast cancer remains an intractable problem, with ∼ 40,000 deaths annually in the United States. Pre-clinical evidence suggests psychosocial stress accelerates cancer progression. Notably, these studies feature injectable tumor models, often in immunocompromised animals exposed to prolonged stress. We have employed a model of spontaneous, metastatic breast cancer, MMTV-PyMT mice, to more closely mimic clinical disease progression. Mice were exposed to a combined stressor featuring chronic social isolation and acute restraint, which activated the hypothalamic-pituitary-adrenal (HPA)-axis and sympathetic nervous system (SNS). Stressed mice were socially isolated during premalignancy. Two weeks later, isolated mice were exposed to 3 days of 2-hour restraint. We hypothesized this stressor would exacerbate tumor progression. Instead, 2 weeks post-restraint, stressed mice had smaller tumors, reduced splenic/lung CD11b+Gr-1+ myeloid-derived suppressor cells, and reduced pro-tumor MMP-2 and TGF-beta1/2 in plasma exosomes. By 3 weeks post-restraint, HPA-axis and SNS activation were still apparent in stressed mice, but no alterations in tumor size, immune populations, exosomal proteins, or lung metastases were detected. Stress-induced reduction in tumor growth suggests an inhibitory neurohormonal pathway linking stress and cancer progression. Psychosocial stress exposure had no long-term impact on progression, despite evidence for an altered neurohormonal environment, suggesting receptor desensitization/resistance may compensate for elevated neurohormones. A deeper understanding of biobehavioral pathways in cancer progression is needed before targeting stress neuroendocrine signaling therapeutically. Funded in part by NCI Contract No. HHSN261200800001E .