Mechanisms of stress signaling in breast cells and of stress-induced breast cancer development. (a) Mechanisms of stress signaling in breast cells. Stress-induced cortisol (C) binding to the glucocorticoid receptor (GR) causes translocation of the GR to the cell nucleus and changes in the expression of apoptotic and DNA repair genes. Some possible protumorigenic mechanisms include loss of GR transactivation at the breast cancer susceptibility gene 1 (BRCA1) promoter, stimulation of activator protein (AP)-1 transrepressing activities, activation of serum and glucocorticoid-regulated kinase-1 (SGK-1), repression of mitogen-activated protein kinase (MAPK) signaling, suppression of inhibitors of apoptosis protein (IAP) degradation, and modulation of the levels of DNA damage sensor and response proteins. Green arrows represent a positive effect, red lines represent a negative effect. (b) A model of stress-induced breast cancer development. The cortisol-activated GR stimulates mammary gland proliferation during development and represses involution. Prolonged presence of cortisol, such as in periods of stress, leads to an increase in both the proproliferative and antiapoptotic effects of the receptor creating transformation-promoting intracellular conditions. FOXO3a, Forkhead transcription factor 3a; MKP-1, mitogen-activated protein kinase phosphatase-1.