Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Int J Cancer. 2014 Sep 1;135(5):1072-84. doi: 10.1002/ijc.28741. Epub 2014 Feb 25.
Exogenous 17β-estradiol (E2) accelerates the progression of ovarian cancer in the transgenic tgCAG-LS-TAg mouse model of the disease. We hypothesized that E2 has direct effects on ovarian cancer cells and this study was designed to determine the molecular mechanisms by which E2 accelerates ovarian tumor progression. Mouse ovarian cancer ascites (MAS) cell lines were derived from tgCAG-LS-TAg mice. Following intraperitoneal engraftment of two MAS cell lines, MASC1 and MASE2, into SCID mice, exogenous E2 significantly decreased the survival time and increased the tumor burden. Microarray analysis performed on MASE2-derived tumors treated with E2 or placebo showed that E2 treatment caused the upregulation of 197 genes and the downregulation of 55 genes. The expression of gene regulated by estrogen in breast cancer 1 (Greb1) was upregulated in mouse tumors treated with E2 and was overexpressed in human ovarian cancers relative to human ovarian surface epithelium, suggesting a role for GREB1 in human ovarian tumor progression. RNA interference-mediated knockdown of GREB1 in MASE2 cells decreased their proliferation rate in vitro and increased survival time in mice engrafted with the cells. These results emphasize the importance of E2 in ovarian tumor progression and identify Greb1 as a novel gene target for therapeutic intervention.
外源性 17β-雌二醇（E2）可加速疾病转基因 tgCAG-LS-TAg 小鼠模型中的卵巢癌进展。我们假设 E2 对卵巢癌细胞有直接影响，本研究旨在确定 E2 加速卵巢肿瘤进展的分子机制。从 tgCAG-LS-TAg 小鼠中获得了小鼠卵巢癌腹水（MAS）细胞系。将两种 MAS 细胞系 MASC1 和 MASE2 经腹腔植入 SCID 小鼠后，外源性 E2 显著缩短了存活时间并增加了肿瘤负担。对用 E2 或安慰剂处理的 MASE2 衍生肿瘤进行的微阵列分析表明，E2 处理导致 197 个基因上调和 55 个基因下调。用 E2 处理的小鼠肿瘤中雌激素反应基因 1（Greb1）的表达上调，并且相对于人卵巢表面上皮，在人卵巢癌中过表达，这表明 GREB1 在人卵巢肿瘤进展中起作用。用 RNA 干扰介导的 GREB1 在 MASE2 细胞中的敲低降低了细胞在体外的增殖率，并增加了植入细胞的小鼠的存活时间。这些结果强调了 E2 在卵巢肿瘤进展中的重要性，并确定了 Greb1 作为治疗干预的新的基因靶标。
