Experimental & Molecular Pathology, 2011, 90(3):257-63.

Genistein Effects on Stromal Cells Determines Epithelial Proliferation in Endometrial Co-Cultures

Brante P. Sampey, Terrence D Lewis, Claire S Barbier, et al

Department of Pathology and Laboratory Medicine, 620 Brinkhous-Bullitt Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599–7525, USA; et al

Background: Estrogen is the leading etiologic factor for endometrial cancer. Estrogen-induced proliferation of endometrial epithelial cells normally requires paracrine growth factors produced by stromal cells. Epidemiologic evidence indicates that dietary soy prevents endometrial cancer, and implicates the phytoestrogen genistein in this effect. However, results from previous studies are conflicting regarding the effects of genistein on hormone responsive cancers.

Methods: The effects of estrogen and genistein on proliferation of Ishikawa (IK) endometrial adenocarcinoma cells were examined in co-cultures of IK cells with endometrial stromal cells, recapitulating the heterotypic cell-to-cell interactions observed in vivo. The roles of estrogen receptor (ER)α and ERβ were evaluated using ERα and ERβ specific agonists. ER activation and cell proliferation in the IK epithelial cells were determined by alkaline phosphatase assay and Coulter counter enumeration, respectively.

Results: Both estrogen and genistein increased estrogen receptor-induced gene activity in IK cells over a range of concentrations. Estrogen alone but not genistein increased IK proliferation in co-cultures. When primed by estrogen treatment, increasing concentrations of genistein produced a biphasic effect on IK proliferation: nM concentrations inhibited estrogen-induced proliferation while μM concentrations increased proliferation. Studies with an ERβ-specific agonist produced similar results. Genistein did not influence the effects of estrogen on IK proliferation in monoculture.

Conclusions: Our study indicates that nutritionally relevant concentrations (nM) of genistein inhibit the proliferative effects of estrogen on endometrial adenocarcinoma cells presumably through activation of stromal cell ERβ. We believe that sub-micromolar concentrations of genistein may represent a novel adjuvant for endometrial cancer treatment and prevention.

美国《实验及分子病理学》，2011年6月

金雀异黄素对基质细胞的作用确定了在共存群落中子宫内膜上皮细胞的增殖

勃朗台 P.山姆帕，特伦斯 D 刘易斯，克莱尔 S 巴比尔等

美国北卡罗来纳大学教堂山分校病理学和实验室药物教研室等

背景︰ 雌激素是子宫内膜癌的主要病因。雌激素诱导子宫内膜上皮细胞增殖一般需要基质细胞产生的旁分泌生长因子。流行病学证据表明大豆可以预防子宫内膜癌，并且这种作用主要由植物雌激素金雀异黄素实现。然而，以往关于金雀异黄素对激素反应癌症影响的研究结果相互矛盾。

方法︰在共培养的子宫内膜间质细胞和IK细胞中检测雌激素和金雀异黄素对石川 (IK) 子宫内膜腺癌细胞增殖的影响，概述体内异型细胞间的相互作用。使用 ERα 和 ERβ 的特定受体激动剂评估雌激素受体 (ER) α 和 ERβ 的作用。分别通过碱性磷酸酶测定和库尔特计数器计数计算在IK上皮细胞中的ER 活化和细胞增殖。

结果︰在IK 细胞中一定浓度范围的雌激素和金雀异黄素都能增加雌激素受体介导的基因活性。单独使用雌激素可以在共培体中增加 IK 的增殖。当事先用雌激素治疗时，提高染料木黄酮的浓度可以产生对 IK 增殖的双向效应︰ nM 浓度抑制雌激素诱导的增殖而 μ M 浓度促进增殖。关于ERβ特异性受体激动剂的研究得到类似的结果。在单一培养物中染料木黄酮不会影响雌激素对 IK 增殖的影响。

结论︰ 我们的研究表明，营养相关浓度 (nM)的 染料木黄酮可能是通过激活基质细胞ERβ来抑制雌激素对子宫内膜腺癌细胞的增殖效应。我们相信毫摩尔浓度的染料木黄酮可能代表一种新型的治疗和预防子宫内膜癌的辅助方法。