Tanaka Y, Kuwabara K, Okazaki T, Fujita T, Oizumi I, Kaiho S, Ogata E
Third Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Oncology. 2000;59 Suppl 1:19-23. doi: 10.1159/000055283.
Estrogen receptor (ER)-positive breast cancers initially respond well to estrogen ablation treatment but finally acquire refractoriness, the phenomenon that is a major clinical problem. Because some breast cancers synthesize estradiol (E(2)) and E(2) synthesis is regulated by gonadotropins in normal ovaries, and because circulating gonadotropins are elevated in postmenopausal women and during estrogen ablation treatment, we hypothesized that gonadotropins might modulate estrogen synthesis/metabolism in breast cancer tissue as well. To test this possibility, MCF-7 cells were treated with dehydroepiandrosterone (DHEA) or human chorionic gonadotropin (hCG; approximately LH), each alone or in combination. Cell growth (3-day treatment) was assayed by the MTT method and estrogen synthesis (24-hour treatment) was measured using the ERE-luciferase reporter system. First, MCF-7 cell growth was stimulated by DHEA in a concentration-dependent manner with a maximal effect at 10(-4) M. Although hCG alone did not have a significant proliferative effect, hCG significantly and dose dependently stimulated MCF-7 cell growth in the presence of a submaximal concentration of DHEA (10(-7 )M). This stimulatory effect of DHEA and hCG was blocked by a pure antiestrogen ICI182,780 and an aromatase inhibitor, arimidex. Using MCF-7 cells transfected with the ERE-luciferase reporter system, hCG treatment was shown to increase ERE-mediated transcription. These results indicate that MCF-7 cells intrinsically converted DHEA into E(2) upon hCG stimulation, then grew their own cells DHEA- and hCG-dependently. We conclude that gonadotropins can act on breast cancer cells and accelerate conversion of DHEA into estrogens, thereby stimulating growth of estrogen-dependent tumor cells. This phenomenon, at least in part, could explain: (1) an increased tissue concentration of E(2) in postmenopausal breast cancer; (2) acquisition of hormone refractoriness during estrogen ablation treatment, and (3) the effectiveness of GnRH antagonist/superagonist in some postmenopausal breast cancer patients.
雌激素受体（ER）阳性乳腺癌最初对雌激素去除治疗反应良好，但最终会产生耐药性，这一现象是一个主要的临床问题。由于一些乳腺癌会合成雌二醇（E₂），且在正常卵巢中E₂的合成受促性腺激素调节，还因为绝经后女性以及雌激素去除治疗期间循环促性腺激素水平会升高，我们推测促性腺激素可能也会调节乳腺癌组织中的雌激素合成/代谢。为了验证这种可能性，我们分别单独或联合使用脱氢表雄酮（DHEA）或人绒毛膜促性腺激素（hCG；近似促黄体生成素）处理MCF-7细胞。通过MTT法检测细胞生长（3天处理），并使用雌激素反应元件 - 荧光素酶报告系统测量雌激素合成（24小时处理）。首先，DHEA以浓度依赖性方式刺激MCF-7细胞生长，在10⁻⁴M时具有最大效应。虽然单独的hCG没有显著的增殖作用，但在亚最大浓度的DHEA（10⁻⁷M）存在时，hCG能显著且剂量依赖性地刺激MCF-7细胞生长。DHEA和hCG的这种刺激作用被纯抗雌激素ICI182,780和芳香化酶抑制剂阿那曲唑阻断。使用转染了雌激素反应元件 - 荧光素酶报告系统的MCF-7细胞，结果显示hCG处理可增加雌激素反应元件介导的转录。这些结果表明，在hCG刺激下，MCF-7细胞内在地将DHEA转化为E₂，然后以DHEA和hCG依赖性方式使自身细胞生长。我们得出结论，促性腺激素可作用于乳腺癌细胞并加速DHEA向雌激素的转化，从而刺激雌激素依赖性肿瘤细胞的生长。这种现象至少可以部分解释：（1）绝经后乳腺癌中E₂的组织浓度增加；（2）雌激素去除治疗期间激素耐药性的产生；以及（3）GnRH拮抗剂/超激动剂在一些绝经后乳腺癌患者中的有效性。
