Estrogen receptor-mediated effects of tamoxifen on human endometrial cancer cells.
Tamoxifen is an estrogen receptor (ER)-antagonist that is widely used for the treatment of breast cancer, although it increases the risk of endometrial cancer. The mechanism mediating the stimulatory effect of tamoxifen on endometrial cancer is presently unknown. In this study we examined the effects of tamoxifen on Ishikawa 3H-12 endometrial cancer cells and MCF-7 breast cancer cells. Ishikawa cell growth was stimulated by 4-hydroxytamoxifen and accompanied by increased transcriptional activity of the endogenous ER. These stimulatory effects did not occur in MCF-7 cells. The relative transcriptional activity of the activation function (AF) 1 domain of ERalpha compared with that of the AF2 domain was 4-fold higher in Ishikawa cells than in MCF-7 cells. Mitogen-activated protein (MAP) kinase, which stimulates the transcriptional activity of AF1, was constitutively activated in Ishikawa cells, but not in MCF-7 cells. These observations suggest that the constitutively activated MAP kinase-signaling pathway in Ishikawa cells enhances the transcriptional activity of ERalpha via the AF1 domain. This ERalpha activation pathway may be involved in the stimulatory effect of tamoxifen on the development and/or progression of endometrial cancer.
Sakamoto
Takako
T
Department of Obstetrics and Gynecology, Teikyo University School of Medicine, 2-11-1 Kaga Itabashi-ku, 173-8605, Tokyo, Japan. takakos@med.teikyo-u.ac.jp
Eguchi
Hidetaka
H
Omoto
Yoko
Y
Ayabe
Takuya
T
Mori
Hiroyuki
H
Hayashi
Shin-ichi
S
D000230:Adenocarcinoma / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology; D002277:Carcinoma / Q000139:chemically induced / Q000473:pathology*; D016889:Endometrial Neoplasms / Q000139:chemically induced / Q000473:pathology*; D004717:Endometrium / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology*; D056921:Nuclear Receptor Coactivator 3; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology*; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D014157:Transcription Factors; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D056921:Nuclear Receptor Coactivator 3