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Difference between genomic actions of estrogen versus raloxifene in human ovarian cancer cell lines
H Sasaki1, J Hayakawa, Y Terai
1Department of Obstetrics and Gynecology, Osaka University Medical School, Yamadaoka, Suita, Osaka, Japan.
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 (ERalpha). 17beta-Estradiol (E2) induced the gene expression of c-Myc and IGF-1 and increased the binding of ERalpha to the AP1 site of the promoters of c-Myc and IGF-1. ERalpha 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 ERalpha 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 ERalpha appear to be dependent on the recruitment of co-regulators.
Insights
Estrogen promotes ovarian cancer progression by activating c-Myc and IGF-1 gene expression via co-activator recruitment. Raloxifene, however, recruits co-repressors, hindering these effects.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Estrogens are implicated in epithelial ovarian cancer progression, but mechanisms remain unclear.
- Selective estrogen receptor modulators (SERMs) have complex effects, and their mechanisms in ovarian cancer are also poorly understood.
Purpose of the Study:
- To elucidate the distinct genomic actions of estrogen and raloxifene in human ovarian cancer cell lines expressing estrogen receptor alpha (ERalpha).
- To investigate the role of co-regulators in mediating these differential effects.
Main Methods:
- Utilized human ovarian cancer cell lines expressing ERalpha.
- Assessed gene expression changes (c-Myc, IGF-1) following treatment with 17beta-estradiol (E2) or raloxifene.
- Performed chromatin immunoprecipitation to evaluate ERalpha binding and co-regulator recruitment to target gene promoters.
- Employed gene silencing techniques (ERalpha, SRC-1) to determine functional significance.
Main Results:
- 17beta-Estradiol (E2) induced c-Myc and IGF-1 expression and ERalpha binding to their promoters, recruiting co-activators (SRC-1, SRC-3, CBP).
- ERalpha silencing blocked E2-stimulated c-Myc expression; SRC-1 silencing inhibited E2-induced c-Myc expression and cell-cycle progression.
- Raloxifene increased ERalpha binding but did not affect c-Myc or IGF-1 expression, instead recruiting co-repressors (HDAC2, N-CoR, SMRT) to the IGF-1 promoter.
Conclusions:
- Genomic actions of estrogen and raloxifene differ significantly in ERalpha-positive ovarian cancer cells.
- Differential recruitment of co-activators versus co-repressors underlies these distinct effects.
- These findings highlight distinct molecular pathways influenced by estrogen and SERMs in ovarian cancer progression.
