Glucocorticoid and Mineralocorticoid Cross-Talk with Progesterone Receptor to Induce Focal Adhesion and Growth Inhibition in Breast Cancer Cells

• Published in: Endocrinology (Philadelphia) 2004-03, Vol.145 (3), p.1314-1321
• Main Authors: Leo, Joyce C. L, Guo, Chunhua, Woon, Chow Thai, Aw, Swee Eng, Lin, Valerie C. L
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Adhesion; Aldosterone; Aldosterone - pharmacology; Biological and medical sciences; Breast cancer; Breast Neoplasms; Cell Division - physiology; Cell Line, Tumor - cytology; Cell Line, Tumor - drug effects; Cell Line, Tumor - physiology; Cell proliferation; Cell spreading; Corticoids; Corticosteroids; Cyclin-dependent kinase inhibitor p21; Dexamethasone; Dexamethasone - pharmacology; Female; Focal Adhesions - physiology; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Glucocorticoid receptors; Glucocorticoids; Glucocorticoids - pharmacology; GTP-binding protein; Hormones; Humans; Hydrocortisone - pharmacology; MAP kinase; Mineralocorticoid receptors; Physiological effects; Progesterone; Progesterone - pharmacology; Receptor Cross-Talk - physiology; Receptors; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Receptors, Mineralocorticoid - genetics; Receptors, Mineralocorticoid - metabolism; Receptors, Progesterone - metabolism; Sex hormones; Steroids; Thyroid; Thyroid gland; Thyroid hormones; Transfection; Triiodothyronine; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2003-0732

Progesterone receptor (PR), glucocorticoid receptor, and mineralocorticoid receptor belong to a subfamily of nuclear receptor superfamily with similar sequence and structural characteristics. Many reports have documented glucocorticoid-like effects of progesterone in various tissues. This study addresses the issue of cross-talk between corticosteroids and PR using PR-transfected MDA-MB-231 cells ABC28 and vector-transfected control cells CTC15. At physiological concentrations, dexamethasone, cortisol, and aldosterone mimic the effects of progesterone by inducing significant growth inhibition, cell spreading, and focal adhesions in PR-positive ABC28 cells. These hormones also induce progesterone-like effects in increasing the expression of p21CIP1/WAF1 protein and decreasing the level of phospho-p42/p44 mAPK. Two lines of evidence suggest that these effects are mediated by cross-talk with PR. First, these compounds do not exhibit the same progesterone-like effects in PR-negative CTC15 cells. Second, PR blocker ZK98299 abolishes their effect on cell spreading and focal adhesion in ABC28 cells. The cross-talk is corticosteroid specific because estradiol and thyroid hormone triiodothyronine have no effect on PR-transfected cells ABC28. It is also interesting to note that dexamethasone induces a small but detectable increase of focal adhesions and limited growth stimulation in vector-transfected cells CTC15. In contrast, progesterone exhibits no detectable effect on CTC15 cells. This study provides evidence that glucocorticoid and mineralocorticoid cross-talk with PR to produce progesterone-like effects in breast cancer cells. Glucocorticoid receptor and PR share some overlapping activity in mediating focal adhesion but not in regulating cell proliferation.