Department of Obstetrics and Gynecology, Center for Integrative Science, University of Chicago, IL 60637, USA.
Gynecol Oncol. 2012 Jan;124(1):134-41. doi: 10.1016/j.ygyno.2011.08.026. Epub 2011 Oct 11.
To test if estrogen promotes carcinogenesis in vitro and in a genetic mouse model of ovarian cancer and whether its effects can be inhibited by a novel selective estrogen receptor modulator (SERM), bazedoxifene.
Bazedoxifene was synthesized and it was confirmed that the drug abrogated the uterine stimulatory effect of 17β-estradiol in mice. To determine if hormones alter tumorigenesis in vivo LSL-K-ras(G12D/+)Pten(loxP/loxP) mice were treated with vehicle control, 17β-estradiol or bazedoxifene. Hormone receptor status of a cell line established from LSL-K-ras(G12D/+)Pten(loxP/loxP) mouse ovarian tumors was characterized using Western blotting and immunohistochemistry. The cell line was treated with hormones and invasion assays were performed using Boyden chambers and proliferation was assessed using MTT assays.
In vitro 17β-estradiol increased both the invasion and proliferation of ovarian cancer cells and bazedoxifene reversed these effects. However, in the genetic mouse model neither treatment with 17β-estradiol nor bazedoxifene changed mean tumor burden when compared to treatment with placebo. The mice in all treatment groups had similar tumor incidence, metastatic nodules and ascites.
While 17β-estradiol increases the invasion and proliferation of ovarian cancer cells, these effects do not translate into increased tumor burden in a genetic mouse model of endometrioid ovarian cancer. Likewise, while the SERM reversed the detrimental effects of estrogen in vitro, there was no change in tumor burden in mice treated with bazedoxifene. These findings demonstrate the complex interplay between hormones and ovarian carcinogenesis.
检测雌激素是否在体外和卵巢癌的遗传小鼠模型中促进致癌作用，以及其作用是否可以被新型选择性雌激素受体调节剂（SERM）巴多昔芬所抑制。
合成了巴多昔芬，并证实该药物可阻断 17β-雌二醇对小鼠子宫的刺激作用。为了确定激素是否会改变体内肿瘤发生，用 vehicle control、17β-雌二醇或巴多昔芬处理 LSL-K-ras(G12D/+)Pten(loxP/loxP)小鼠。使用 Western blot 和免疫组化技术对从 LSL-K-ras(G12D/+)Pten(loxP/loxP)小鼠卵巢肿瘤中建立的细胞系的激素受体状态进行了表征。用激素处理细胞系，并使用 Boyden 室进行侵袭测定，用 MTT 测定法评估增殖。
在体外，17β-雌二醇增加了卵巢癌细胞的侵袭和增殖，而巴多昔芬则逆转了这些作用。然而，在遗传小鼠模型中，与安慰剂相比，用 17β-雌二醇或巴多昔芬治疗并未改变平均肿瘤负担。所有治疗组的小鼠肿瘤发生率、转移结节和腹水均相似。
虽然 17β-雌二醇增加了卵巢癌细胞的侵袭和增殖，但这些作用并未转化为子宫内膜样卵巢癌遗传小鼠模型中肿瘤负担的增加。同样，虽然 SERM 逆转了雌激素在体外的有害作用，但用巴多昔芬治疗的小鼠肿瘤负担没有变化。这些发现表明激素与卵巢癌发生之间存在复杂的相互作用。
