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

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.