Effects of oral contraceptives or a gonadotropin-releasing hormone agonist on ovarian carcinogenesis in genetically engineered mice.
Effects of oral contraceptives or a gonadotropin-releasing hormone agonist on ovarian carcinogenesis in genetically engineered mice.
复制标题
口服避孕药或促性腺激素释放激素激动剂对基因工程小鼠卵巢癌发生的影响。
DOI：
10.1158/1940-6207.capr-08-0236
复制
发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Lengyel E
中科院分区：
文献类型：
--
作者：
Romero IL;Gordon IO;Jagadeeswaran S;Mui KL;Lee WS;Dinulescu DM;Krausz TN;Kim HH;Gilliam ML;Lengyel E
尽管联合口服避孕药(OC)能够降低卵巢癌风险的流行病学证据令人信服，但这种效果背后的生物学机制在很大程度上尚不清楚。我们进行了这项研究，以确定OC是否也影响遗传小鼠模型中卵巢癌的发生，如果是，则调查潜在的保护作用的机制。LSL-K-RasG12D/+PtenloxP/loxP小鼠分别给予雌二醇和去甲肾上腺素联合治疗，或单用去甲肾上腺素或促性腺激素释放激素(GnRH)激动剂。与安慰剂(上皮肿瘤重量，−80%)相比，联合OC的平均总肿瘤重量减少了29%。单用去甲肾上腺素能使平均总肿瘤重量减少42%(上皮性肿瘤重量，−46%)，而促性腺激素释放激素激动剂使平均总肿瘤重量增加71%(上皮性肿瘤重量，+150%)。肿瘤大小的巨大差异影响了这些变化的P值，这些变化在统计学上没有显著意义。尽管如此，OC的减少与流行病学数据显示OC的保护作用是一致的。与卵巢癌相关的基质金属蛋白酶2活性降低，提示卵巢癌可能通过降低蛋白水解酶活性而影响卵巢癌的发生。相反，OC增加了从小鼠肿瘤建立的K-ras/Pten卵巢癌细胞系的侵袭力，这表明OC激素，特别是雌激素，可能在疾病过程中具有有害的影响。我们的研究结果支持进一步研究OC预防卵巢癌的作用和机制。
Although epidemiological evidence for the ability of combined oral contraception (OC) to reduce the risk of ovarian cancer is convincing, the biological mechanisms underlying this effect are largely unknown. We conducted the present study to determine if OC also influences ovarian carcinogenesis in a genetic mouse model and, if so, to investigate the mechanism underlying the protective effect. LSL-K-rasG12D/+PtenloxP/loxP mice were treated with ethinyl estradiol plus norethindrone, contraceptive hormones commonly used in combined OC, or norethindrone alone, or a gonadotropin-releasing hormone (GnRH) agonist. The combined OC had a 29% reduction in mean total tumor weight compared with placebo (epithelial tumor weight, −80%). Norethindrone alone reduced mean total tumor weight by 42% (epithelial tumor weight, −46%), and the GnRH agonist increased mean total tumor weight by 71% (epithelial tumor weight, +150%). Large variations in tumor size affected the P-values for these changes, which were not statistically significant. Nonetheless, the OC reductions are consistent with the epidemiologic data indicating a protective effect of OC. Matrix metalloproteinase 2 activity was decreased in association with OC, indicating that OC may affect ovarian carcinogenesis by decreasing proteolytic activity, an important early event in the pathogenesis of ovarian cancer. In contrast, OC increased invasion in a K-ras/Pten ovarian cancer cell line established from the mouse tumors, suggesting that OC hormones, particularly estrogen, may have a detrimental effect after the disease process is underway. Our study results support further investigation of OC effects and mechanisms for ovarian cancer prevention.