Stress is a risk factor for tumor progression: investigation of the neuroendocrine , immune and genetic markers in a mouse model

Epidemiological evidence and basic research clearly indicate that stress can affect breast cancer pathogenesis at multiple levels (initiation, tumor growth, and metastasis), although our understanding of the underlying mechanisms is in its infancy. Stress may impair immunosurveillance and can cause persistent inflammation that, during critical life phases, might affect tumor progression. Stress physiology overlaps to a great extent in humans and mice, thus preclinical models can guide and refine hypothesis-driven clinical research questions. In this study we used stressors of different lengths and strengths known to affect neuro-immune functioning to model the diverse experiences of the patients. In a first study we investigated the effect of brief -7 - vs. prolonged -21 days – restraint stress as a risk factor for tumor progression in 4-month-old C57 male mice. Results indicate reduced corticosterone levels on day 7 (short-term stress), followed by an increase on day 21 (long-term procedure). This response was associated with an inverted “U” shape activation of the immune function, with an increase in cytokine levels (TNF-alpha, IL-6 and IL-10) and in hippocampal Brain-Derived Neurotrophic Factor (BDNF) levels. In a second study, gene by environment interactions were studied in a transgenic model of breast cancer (TgNeu). Here we tested the effects of restraint stress in female subjects previously isolated from their conspecifics for a prolonged period of time (6 months). This procedure resulted in a more marked immune response in those subjects bearing a genetic susceptibility, TgNeu mice showing greater splenocyte apoptosis, an effect amplified by social isolation and acute stress exposure. Neuroendocrine and histopatological analysis are in progress to assess changes in these parameters. Results from these studies indicate that environmental factors can contribute, together with the genetic makeup, to determine susceptibility to tumor onset and progression.