Stress and breast cancer: from epidemiology to molecular biology

Abstract

Stress exposure has been proposed to contribute to the etiology of breast cancer. However, the validity of this assertion and the possible mechanisms involved are not well established. Epidemiologic studies differ in their assessment of the relative contribution of stress to breast cancer risk, while physiological studies propose a clear connection but lack the knowledge of intracellular pathways involved. The present review aims to consolidate the findings from different fields of research (including epidemiology, physiology, and molecular biology) in order to present a comprehensive picture of what we know to date about the role of stress in breast cancer development.

Figure 1

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.

Figure 2

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.