Li J J, Hou X, Bentel J, Yazlovitskaya E M, Li S A
Kansas Cancer Institute, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7312, USA.
Carcinogenesis. 1998 Mar;19(3):471-7. doi: 10.1093/carcin/19.3.471.
Ethinylestradiol (EE) has evident paradoxical effects on cancer risk for human breast and hepatic cancer which parallel in some respects its effects on estrogen-induced neoplasms in the hamster kidney and liver. EE has been shown to be only weakly carcinogenic in the hamster kidney, but the most potent carcinogenic estrogen in the hamster liver following prolonged treatment. Unexpectedly, when EE and potent carcinogenic estrogens, such as diethylstilbestrol (DES), 17beta-estradiol (E2) and Moxestrol (MOX), are administered concomitantly, estrogen-induced carcinogenesis in the kidney is completely prevented. In studying this novel finding, we found that, compared with E2 exposure alone, EE at 0.05 and 1.0 nM significantly (P < 0.001) inhibited the rise in proliferation of cultured primary hamster proximal renal tubular (PRT) cells in the presence of E2 (1.0 nM). Consistent with these findings, combined EE + DES treatment for 5.0 months reduced hamster kidney c-myc, c-fos and c-jun RNA expression to 43, 37 and 52%, respectively, compared with levels observed after DES treatment alone. Interestingly, TAM + DES treatment for the same period also resulted in the same low level of RNA expression of these proto-oncogenes. c-MYC, c-FOS and c-JUN protein products were comparably reduced after either EE + DES or TAM + DES treatment. It appears that c-fos expression and c-FOS protein levels in the hamster kidney were more responsive to TAM inhibition. These data demonstrate that EE possesses unique anti-tumorigenic properties in vivo in the hamster kidney. Additionally, the observed anti-estrogen-like effect of EE on cell proliferation of cultured PRT cells suggests that EE may interfere critically with estrogen receptor (ER)-mediated mitogenic pathway(s) affected by potent carcinogenic estrogens, thus preventing subsequent gene dysregulation and, hence, tumor development. Based on competition studies, the differential binding of EE to hamster kidney ER relative to that of the other estrogens (E2, DES, MOX) appears not to contribute to the prevention of estrogen carcinogenesis at this organ site by EE.
炔雌醇（EE）对人类乳腺癌和肝癌的癌症风险具有明显的矛盾效应，在某些方面与其对仓鼠肾脏和肝脏中雌激素诱导的肿瘤的影响相似。已表明EE在仓鼠肾脏中仅具有弱致癌性，但在长期治疗后是仓鼠肝脏中最有效的致癌雌激素。出乎意料的是，当同时给予EE和强效致癌雌激素，如己烯雌酚（DES）、17β-雌二醇（E2）和莫昔司琼（MOX）时，可完全预防肾脏中雌激素诱导的致癌作用。在研究这一新颖发现时，我们发现，与单独暴露于E2相比，在存在E2（1.0 nM）的情况下，0.05和1.0 nM的EE显著（P < 0.001）抑制了培养的原代仓鼠近端肾小管（PRT）细胞增殖的增加。与这些发现一致，与单独DES治疗后观察到的水平相比，EE + DES联合治疗5.0个月使仓鼠肾脏c-myc、c-fos和c-jun RNA表达分别降至43%、37%和52%。有趣的是，同期的TAM + DES治疗也导致这些原癌基因的RNA表达水平同样降低。EE + DES或TAM + DES治疗后，c-MYC、c-FOS和c-JUN蛋白产物均相应减少。似乎仓鼠肾脏中的c-fos表达和c-FOS蛋白水平对TAM抑制更敏感。这些数据表明EE在仓鼠肾脏体内具有独特的抗肿瘤特性。此外，观察到的EE对培养的PRT细胞增殖的抗雌激素样作用表明，EE可能严重干扰强效致癌雌激素影响的雌激素受体（ER）介导的有丝分裂途径，从而防止随后的基因失调，进而预防肿瘤发展。基于竞争研究，EE与仓鼠肾脏ER的差异结合相对于其他雌激素（E2、DES、MOX）似乎并不是EE预防该器官部位雌激素致癌作用的原因。
