MODULATION OF STAT 5A SIGNAL TRANSDUCTION IN BREAST CANCER CELL LINES RESTORE MESENCHYMAL-EPITHELIAL TRANSITION

Abstract

of breast cancer, although only approximately 25% of patients respond to glucocorticoid treatment alone. Better understanding of the molecular mechanisms underlying the therapeutic responses of breast cancer to glucocorticoid treatment may lead to new selection criteria and improve response rates. Experimental evidence in rodents has indicated that glucocorticoid treatment protects against the mammary tumor promoting effect of prolactin, and a molecular interaction between glucocorticoids and prolactin downstream of prolactin receptor activation has been suggested. Recently, we have discovered a new role of Stat5a as tumor suppression gene for breast cancer invasion that inhibited breast cancer stem cell characteristics in primary tumor and human cell lines. We now report that dexamethasone can up-regulate prolactin signaling via Stat5a in certain human breast cancer cell lines. Pretreatment of the human breast cancer cell line T47D for 2-4 days led to marked enhancement of prolactin activation of the transcription factor Stat5a. Thus, dexamethasone induced a qualitative change in prolactin signals from exclusive Stat5b activation to combined recruitment of Stat5a and Stat5b, with extensive heterodimerization of the two transcription factors. This dexamethasone-dependent change in prolactin signals was associated with stimulation of terminal differentiation markers in T47D cells. Interestingly, prolactin activation of mitogen-activated protein kinases and growth-related genes c-fos, c-jun and c-myc was not affected by dexamethasone. A similar, but less marked, stimulation by dexamethasone pretreatment of prolactin-activated Stat5a was seen in MCF-7 cells. In contrast, Stat5a expression was lost in the undifferentiated, estrogen receptor (ER)-negative BT-20 and SKBr3 cell lines, and could not be rescued by dexamethasone. In the nearnormal mammary cell lines, HC11 and MCF-10A, equal levels of Stat5a and Stat5b were expressed in a dexamethasone-independent manner. These studies identify Stat5a as a target for dexamethasone regulation with potential importance for inhibition of tumor metastasis and restore mesenchymal-epithelial transition (MET) of certain mammary cancers, and may help explain the variable response rate of breast cancer patients to glucocorticoid treatment.