Hydrocortisone down-regulates the tumor suppressor gene BRCAI in mammary cells: A possible molecular link between stress and breast cancer

Psychological stress has been correlated with breast cancer development in numerous epidemiological studies. However, physiological and molecular models which may account for this association are not readily available. We have found that the stress hormone hydrocortisone (cortisol) down-regulates the expression of the breast cancer susceptibility gene BRCAI in the nonmalignant mouse mammary cell line EPH4. This effect is concentration-dependent, is reliant on the continuous presence of hydrocortisone, and is not affected by the addition of lactogenic hormones, or growth conditions. Hydrocortisone was also found to negate a known positive effect of estrogen on BRCAI expression and, therefore, may interfere with estrogen-related signaling in mammary epithelial cells. The repressive effect of hydrocortisone is diminished or lost in the mouse mammary lines HC-II and SPI, respectively, suggesting regulation of the BRCAI may differ between lines. We have uncovered two promoter regulatory sites, which are involved in BRCAI regulation by hydrocortisone, namely the RIBS and UP regulatory elements. Binding of the transcription factor GABP to both sites is lost upon hydrocortisone addition, though the levels of these factors are not altered by hydrocortisone treatment. Because BRCAI activity is important for a number of intracellular pathways involved in prevention of tumorigenesis, its observed down-regulation may represent a novel molecular mechanism for cortisol's involvement in breast cancer development. (C) 2008 Wiley-Liss, Inc.