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 ductal and acinar epithelium of glandular organs, such as the breast, exert multiple paracrine suppressive effects on incipient and developing cancers that arise from this epithelium. Myoepithelial cells and derived cell lines (HMS 1-6) exert these effects through the secretion of a number of different effector molecules that exert anti-invasive, anti-proliferative, and anti-angiogenic activities. Since previous basic and clinical studies have examined the role of estrogen agonists and antagonists on human breast cancer cells and because issues of hormone replacement therapy (HRT) and tamoxifen chemoprevention are such timely issues in breast cancer, we wondered whether or not hormonal manipulations might affect myoepithelial cells in vitro as far as their paracrine suppressive activities on breast cancer were concerned. The present in vitro study demonstrates that treatment of myoepithelial cells with tamoxifen but not 17beta-estradiol increases both maspin secretion and invasion-blocking ability. Furthermore tamoxifen but not 17beta-estradiol increases inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production by myoepithelial cells when they are co-cultured with conditioned media from or breast carcinoma cells directly. This increased myoepithelial NO exerts both autocrine and paracrine antiproliferative effects which can be blocked by inhibition of iNOS. 17beta-Estradiol, however, competes with all of these suppressive effects of tamoxifen suggesting that the mechanism of tamoxifen action is estrogen receptor mediated. Myoepithelial cells lack ER-alpha but express ER-beta. Tamoxifen, but not 17beta-estradiol, increases AP-1 CAT but not ERE-CAT activity. Again, 17beta-estradiol competes with the transcription-activating effects of tamoxifen. These experiments collectively suggest that the actions of tamoxifen on the increased secretion of maspin and increased production of NO by myoepithelial cells are mediated through ER-beta and the transcription-activation of an ER-dependent AP-1 response element.
Shao
Z M
ZM
Department of Pathology, UCLA School of Medicine, CA 90024, Los Angeles, CA 90024, USA.
Radziszewski
W J
WJ
Barsky
S H
SH
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D018450:Disease Progression; D004847:Epithelial Cells / Q000187:drug effects; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D011233:Precipitin Tests; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000378:metabolism; D015843:Serpins / Q000187:drug effects / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D011506:Proteins; C085344:SERPIN-B5; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D013629:Tamoxifen; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II