Role of cortisol in mammary gland development. The role of cortisol is shown for the different post-embryonic developmental stages of the mammary gland. Other hormones involved in the different developmental stages are also listed. Estrogen and progesterone promote ductal system proliferation during puberty. However, the DNA binding function of the glucocorticoid receptor also appears to be required. During pregnancy, cortisol contributes to lobuloalveolar development of the mammary gland, in conjunction with estrogen and progesterone. Prolactin and cortisol prepare the mammary cells for lactation and stimulate milk protein production following parturition. In addition, cortisol contributes to the maintenance of lactation by suppressing involution. ER, endoplasmic reticulum.

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.