Raloxifene plus 17beta-estradiol inhibits proliferation of primary cultured vascular smooth muscle cells and human mammary endothelial cells via the janus kinase/signal transducer and activator of transcription3 cascade.
Long-term use of estrogen replacement therapy increases the risk of breast cancer. Presently, we investigated the effects and mechanisms of Raloxifene, a second generation selective estrogen receptor modulator, plus 17beta-estradiol on the proliferation of primary cultured vascular smooth muscle cells (VSMC) and human mammary endothelial cells (HMEC). Raloxifene plus 17beta-estradiol inhibited angiotensin II-induced VSMC proliferation and rapid phosphorylation of STAT(3); these effects were blocked by AG490, the janus kinase/signal transducer and activator of transcription3 (JAK/STAT(3)) inhibitor. STAT(3) production was not affected. In primary cultured HMEC, immunofluorescence identified the ERbeta subtype, but not the ERalpha subtype, in the nucleus. Raloxifene plus 17beta-estradiol inhibited 17beta-estradiol-induced proliferation of HMEC. Western blot analysis established that Raloxifene attenuated the 17beta-estradiol-induced phosphorylation of STAT(3), and that this effect was blocked by AG490. We conclude that Raloxifene plus 17beta-estradiol inhibits the proliferation of VSMC and HMEC through the JAK/STAT(3) cascade, which in primary cultured HMEC may be implemented through ERbeta.
Wang
Ting Huai
TH
Department of Physiology, Sun Yat-Sen Medical College, Sun Yat-Sen University, Guang Zhou 510080, People's Republic of China. wangth@mail.sysu.edu.cn
Xiang
Qiu Ling
QL
Chen
Jian Wen
JW
Pan
Hong
H
Cui
Yu Hong
YH
D000804:Angiotensin II; D000818:Animals; D015153:Blotting, Western; D001940:Breast / Q000166:cytology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects; D004958:Estradiol / Q000009:adverse effects / Q000494:pharmacology*; D047629:Estrogen Receptor beta; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D053612:Janus Kinases / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D020032:Tyrphostins
D047629:Estrogen Receptor beta; D050796:STAT3 Transcription Factor; D020845:Selective Estrogen Receptor Modulators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000804:Angiotensin II; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D053612:Janus Kinases