Abstract
BackgroundEstrogen receptor (ER) β has been suggested to affect ovarian carcinogenesis. We examined the effects of four ERβ agonists on proliferation and gene expression of two ovarian cancer cell lines.MethodsOVCAR-3 and OAW-42 ovarian cancer cells were treated with the ERβ agonists ERB-041, WAY200070, Liquiritigenin and 3β-Adiol and cell growth was measured by means of the Cell Titer Blue Assay (Promega). ERβ expression was knocked down by transfection with specific siRNA. Additionally, transcriptome analyses were performed by means of Affymetrix GeneChip arrays. To confirm the results of DNA microarray analysis, Western blot experiments were performed.ResultsAll ERβ agonists tested significantly decreased proliferation of OVCAR-3 and OAW-42 cells at a concentration of 10 nM. Maximum antiproliferative effects were induced by flavonoid Liquiritigenin, which inhibited growth of OVCAR-3 cells by 31.2% after 5 days of treatment, and ERB-041 suppressing proliferation of the same cell line by 29.1%. In OAW-42 cells, maximum effects were observed after treatment with the ERβ agonist WAY200070, inhibiting cell growth by 26.8%, whereas ERB-041 decreased proliferation by 24.4%. In turn, knockdown of ERβ with specific siRNA increased cell growth of OAW-42 cells about 1.9-fold. Transcriptome analyses revealed a set of genes regulated by ERβ agonists including ND6, LCN1 and PTCH2, providing possible molecular mechanisms underlying the observed antiproliferative effects.ConclusionIn conclusion, the observed growth-inhibitory effects of all ERβ agonists on ovarian cancer cell lines in vitro encourage further studies to test their possible use in the clinical setting.
Highlights
Estrogen receptor (ER) β has been suggested to affect ovarian carcinogenesis
Estrogen receptor beta (ERβ) agonists decreased proliferation of OVCAR-3 and OAW-42 cells OVCAR3 and OAW-42 cells were treated with four different ERβ agonists, ERB-041, WAY-200070, Liquiritigenin and 3β-Adiol
We decided to test this concentration only, because the EC50 values for ERβ binding of all drugs are in the low nanomolar range, and we wanted to rule out activation of ERα by higher drug concentrations, which could be able to increase proliferation
Summary
We examined the effects of four ERβ agonists on proliferation and gene expression of two ovarian cancer cell lines. Steroid hormones have an influence on ovarian cancer cells [3] and it has been shown that 40– 60% of ovarian cancers express estrogen receptor (ER) α [4, 5]. In advanced stages the selective estrogen receptor modulator tamoxifen is used in patients as a well-. Little is known about the molecular mechanisms of ERβ function in ovaries and ovarian cancers. It has been shown that both receptor types exert different biological functions [10, 11]. Given that ERβ is able to counteract ERα signaling in some settings, loss of ERβ is thought to enhance ERα-mediated proliferation of hormone-dependent cancer cells [12]. The Schüler-Toprak et al BMC Cancer (2017) 17:319 influence of ERb signaling on apoptosis pathways has been shown [13]
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