Bombesin and Glucocorticoids Stimulate Human Breast Cancer Cells to Produce Endothelin, a Paracrine Mitogen for Breast Stromal Cells1

Human breast cancer cells have been recently reported to produce endothelin (ET) 1. To investigate the potential regulation of ET produc tion in breast cancer cells, we have measured the release of ET-like immunoreactivity from the T47D cell line in response to various paracrine/endocrine factors. Bombesin (0.1 ¿IM) and Cortisol (l /IM)stimulated maximal respective increases in IR-ET release to 580 and 369% of basal values after 6 h. The responses to cortisol and bombesin were additive. The response to bombesin was dose dependent with a median effective dose around 1 IIMand was inhibited by the receptor antagonist [Leu'3-i/<CH2NH-Leu'4|bombesin. Pretreatment of T47D cells with pertussis toxin had no effect on bombesin-induced inositol lipid hydrolysis but inhibited ET-like immunoreactivity release in response to bombesin in the presence of glucocorticoid, by 56%. I I -I (10 nivi) and insulin-like growth factor (10 ng/ml) stimulated modest separate increases in DNA synthesis in human breast fibroblasts of 35 and 71%, respectively, but together exhibited a strong synergistic response to 905% of control values. This in vitro study demonstrates the potential for bombesin and glucocorticoid to regulate ET production in human breast cancer cells, which may in turn have a paracrine influence on neighboring stromal cell function.