Functional repression of estrogen receptor a by arsenic trioxide in human breast cancer cells.
When estrogen binds its receptor (ER), it becomes a potent mitogen in a number of target tissues including the mammary gland where it plays an important role in the pathogenesis of mammary carcinoma. Arsenic trioxide (AS2O3), a clinically effective agent against acute promyelocytic leukemia, has been shown to induce apoptosis in a variety of cancer cells in vitro. Here, we investigated the effects of AS2O3 on the growth of two ER-positive breast cancer cell lines, MCF7 and T47D in vitro. We found that higher doses of AS2O3 dramatically reduced the survival of these two breast cancer cell lines while lower doses of AS2O3 significantly inhibited the expression of estrogen receptor alpha (ER-alpha), but did not effect ER-beta expression. The ER-alpha expression is totally restored when AS2O3 is absent for 24 hours. Using a reporter gene controlled by ER, we further demonstrated that AS2O3 strongly-repressed 17beta-estradiol (E2) stimulated-transcriptional activation. Moreover, AS2O3 abolished transcriptional induction of the estrogen responsive gene pS2 mediated by E2. These results indicated that AS2O3 specifically inhibits expression and signaling pathway of the ER-alpha. We suggest that AS2O3 in combination with other methods might provide a novel therapeutic approach for ER-alpha-positive breast cancer.
Chen
Gui-Cai
GC
School of Life Sciences, Zhejian University, Hangzhou, PR China.
Guan
Li-Shuang
LS
Hu
Wei-Lian
WL
Wang
Zhao-Yi
ZY
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006801:Humans; D010087:Oxides / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; D001152:Arsenicals; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010087:Oxides; D011506:Proteins; D011960:Receptors, Estrogen; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D000077237:Arsenic Trioxide