Difference between genomic actions of estrogen versus raloxifene in human ovarian cancer cell lines

doi:doi:10.1038/sj.onc.1210926

Oncogene (2008) 27, 2737–2745; doi:10.1038/sj.onc.1210926; published online 14 January 2008

Difference between genomic actions of estrogen versus raloxifene in human ovarian cancer cell lines

H Sasaki³, J Hayakawa¹, Y Terai³, M Kanemura³, A Tanabe-Kimura³, H Kamegai³, H Seino-Noda¹, S Ezoe², I Matsumura², Y Kanakura², M Sakata¹, K Tasaka¹ and M Ohmichi³

¹Department of Obstetrics and Gynecology, Osaka University Medical School, Yamadaoka, Suita, Osaka, Japan
²Department of Hematology and Oncology, Osaka University Medical School, Yamadaoka, Suita, Osaka, Japan
³Osaka Medical College, Daigakumachi, Takatsuki, Osaka, Japan

Correspondence: Dr M Ohmichi, Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigakutyou, Takatsuki, Osaka, 569-8686, Japan. E-mail: masa@gyne.med.osaka-u.ac.jp

Received 16 March 2006; Revised 10 September 2007; Accepted 12 September 2007; Published online 14 January 2008.

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Abstract

Although there is growing evidence that estrogens promote tumor progression in epithelial ovarian cancer, the molecular mechanisms accounting for this are still unclear. Selective estrogen receptor modulators (SERMs) mimic estrogen action in certain tissues while opposing it in others. The molecular mechanisms of the effects of SERMs such as raloxifene on the tumor progression of epithelial ovarian cancer are also still unclear. Here, we show that various genomic actions of estrogen differ from those of raloxifene in human ovarian cancer cell lines expressing estrogen receptor alpha (ER alpha ). 17 beta -Estradiol (E2) induced the gene expression of c-Myc and IGF-1 and increased the binding of ER alpha to the AP1 site of the promoters of c-Myc and IGF-1. ER alpha silencing abolished the E2-stimulated c-Myc expression. E2 induced the recruitment of co-activators such as SRC-1, SRC-3 and CBP to the promoters of c-Myc and IGF-1, and SRC-1 silencing abolished both the E2-stimulated c-Myc expression and cell-cycle progression. In contrast, although raloxifene increased the binding of ER alpha to the AP1 site of the promoters of c-Myc and IGF-1, raloxifene had no effect on the gene expression of c-Myc or IGF-1. Raloxifene induced the recruitment of co-repressors such as HDAC2, N-CoR and SMRT to the promoter of IGF-1. Thus, the difference between the genomic actions exerted by estrogen and raloxifene in human ovarian cancer cell lines expressing ER alpha appear to be dependent on the recruitment of co-regulators.