Institut National de la Santé et de la Recherche Médicale, U844, University of Montpellier I, Montpellier F-34091, France.
PLoS One. 2012;7(9):e44787. doi: 10.1371/journal.pone.0044787. Epub 2012 Sep 6.
Ovarian cancer is the gynecological cancer exhibiting the highest morbidity and improvement of treatments is still required. Previous studies have shown that Estrogen-receptor beta (ERβ) levels decreased along with ovarian carcinogenesis. Here, we present evidence that reintroduction of ERβ in BG-1 epithelial ovarian cancer cells, which express ERα, leads in vitro to a decrease of basal and estradiol-promoted cell proliferation. ERβ reduced the frequency of cells in S phase and increased the one of cells in G2/M phase. At the molecular level, we found that ERβ downregulated total retinoblastoma (Rb), phosphorylated Rb and phospho-AKT cellular content as well as cyclins D1 and A2. In addition, ERβ had a direct effect on ERα, by strongly inhibiting its expression and activity, which could explain part of the anti-proliferative action of ERβ. By developing a novel preclinical model of ovarian cancer based on a luminescent orthotopic xenograft in athymic Nude mice, we further revealed that ERβ expression reduces tumor growth and the presence of tumor cells in sites of metastasis, hence resulting in improved survival of mice. Altogether, these findings unveil a potential tumor-suppressor role of ERβ in ovarian carcinogenesis, which could be of potential clinical relevance for the selection of the most appropriate treatment for patients.
卵巢癌是妇科癌症中发病率最高的一种，仍需要改善治疗方法。先前的研究表明，雌激素受体β (ERβ) 水平随着卵巢癌的发生而降低。在这里，我们提供的证据表明，在表达 ERα 的 BG-1 上皮性卵巢癌细胞中重新引入 ERβ，导致体外基础和雌二醇促进的细胞增殖减少。ERβ 降低了 S 期细胞的频率，并增加了 G2/M 期细胞的频率。在分子水平上，我们发现 ERβ 下调了总视网膜母细胞瘤 (Rb)、磷酸化 Rb 和磷酸化 AKT 细胞含量以及细胞周期蛋白 D1 和 A2。此外，ERβ 对 ERα 有直接影响，强烈抑制其表达和活性，这可以解释 ERβ 部分的抗增殖作用。通过在裸鼠中建立基于发光原位异种移植的新型临床前卵巢癌模型，我们进一步揭示 ERβ 表达降低了肿瘤生长和转移部位肿瘤细胞的存在，从而提高了小鼠的存活率。总之，这些发现揭示了 ERβ 在卵巢癌发生中的潜在肿瘤抑制作用，这可能对为患者选择最合适的治疗方法具有潜在的临床意义。
