Tamoxifen enhances myoepithelial cell suppression of human breast carcinoma progression in vitro by two different effector mechanisms

Our previous studies have indicated that myoepithelial cells surrounding du ctal and acinar epithelium of glandular organs, such as the breast, exert m ultiple paracrine suppressive effects on incipient and developing cancers t hat arise from this epithelium. Myoepithelial cells and derived cell lines (HMS 1-6) exert these effects through the secretion of a number of differen t effector molecules that exert anti-invasive, anti-proliferative, and anti -angiogenic activities. Since previous basic and clinical studies have exam ined the role of estrogen agonists and antagonists on human breast cancer c ells and because issues of hormone replacement therapy (HRT) and tamoxifen chemoprevention are such timely issues in breast cancer, we wondered whethe r or not hormonal manipulations might affect myoepithelial cells in vitro a s far as their paracrine suppressive activities on breast cancer were conce rned. The present in vitro study demonstrates that treatment of myoepitheli al cells with tamoxifen but not 17 beta -estradiol increases both maspin se cretion and invasion-blocking ability. Furthermore tamoxifen but not 17 bet a -estradiol increases inducible nitric oxide synthase (iNOS) expression an d nitric oxide (NO) production by myoepithelial cells when they are co-cult ured with conditioned media from or breast carcinoma cells directly. This i ncreased myoepithelial NO exerts both autocrine and paracrine antiprolifera tive effects which can be blocked by inhibition of iNOS. 17 beta -Estradiol , however, competes with all of these suppressive effects of tamoxifen sugg esting that the mechanism of tamoxifen action is estrogen receptor mediated . Myoepithelial cells lack ER-alpha but express ER-beta. Tamoxifen, but not 17 beta -estradiol, increases AP-1 CAT but not ERE-CAT activity. Again, 17 beta -estradiol competes with the transcription-activating effects of tamo xifen. These experiments collectively suggest that the actions of tamoxifen on the increased secretion of maspin and increased production of NO by myo epithelial cells are mediated through ER-beta and the transcription-activat ion of an ER-dependent AP-1 response element. (C) 2000 Elsevier Science Ire land Ltd. All rights reserved.