van der Burg B, Kalkhoven E, Isbrücker L, de Laat S W
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht.
J Steroid Biochem Mol Biol. 1992 Jun;42(5):457-65. doi: 10.1016/0960-0760(92)90257-j.
The effect was studied of four different synthetic progestins (Org 30659, gestodene, 3-ketodesogestrel and levonorgestrel) on the proliferation of the 17 beta estradiol (E2)-dependent human breast cancer cell line MCF7. All progestins were found to stimulate proliferation, but only at high pharmacological dosages. Moreover, like estrogens the progestins at high concentrations synergistically stimulated MCF7 cell proliferation together with low concentrations of insulin. This stimulatory effect could be blocked by antiestrogens, but not by antiglucocorticoids and antiprogestins. This suggests that growth stimulation by these progestins (or their metabolites) occurs through crossreaction with the E2 receptor (ER). This is confirmed by the observation that the strong synthetic progestin Org 2058 does not stimulate proliferation. The absence of a progesterone receptor (PR)-mediated growth response seems not to be due to aberrant PR expression in these cells; 27,000 receptors (Kd 1.7 x 10(-10)M) per cell were present under growth-assay conditions. Growth stimulation by E2 in the absence or presence of insulin, is slightly inhibited or unaffected by the progestins, respectively. Our data do not support a role for the recently identified gestodene binding sites [Colletta et al., J. Steroid Biochem. 33 (1989) 1055-1061] in mediating gestodene effects on breast cancer cells: gestodene and 3-ketodesogestrel, a compound that does not bind to these gestodene binding sites, showed a similar biological activity. The effects of the progestins on the MCF7 breast cancer cell line, indicate that the use of these compounds at very high concentrations may be unfavourable, but do not support a role for them in directly stimulating breast tumor proliferation at the low progestin concentration which are reached in the serum in oral contraceptive users.
研究了四种不同的合成孕激素（Org 30659、孕二烯酮、3-酮去氧孕烯和左炔诺孕酮）对依赖17β-雌二醇（E2）的人乳腺癌细胞系MCF7增殖的影响。发现所有孕激素均能刺激增殖，但仅在高药理剂量下。此外，与雌激素一样，高浓度的孕激素与低浓度的胰岛素协同刺激MCF7细胞增殖。这种刺激作用可被抗雌激素阻断，但不能被抗糖皮质激素和抗孕激素阻断。这表明这些孕激素（或其代谢产物）的生长刺激作用是通过与E2受体（ER）交叉反应而发生的。这一点通过观察到强效合成孕激素Org 2058不刺激增殖得到了证实。缺乏孕激素受体（PR）介导的生长反应似乎不是由于这些细胞中PR表达异常所致；在生长测定条件下，每个细胞存在27000个受体（解离常数为1.7×10^(-10)M）。在不存在或存在胰岛素的情况下，E2的生长刺激作用分别被孕激素轻微抑制或不受影响。我们的数据不支持最近发现的孕二烯酮结合位点[科莱塔等人，《类固醇生物化学杂志》33（1989）1055-1061]在介导孕二烯酮对乳腺癌细胞的作用中起作用：孕二烯酮和3-酮去氧孕烯（一种不与这些孕二烯酮结合位点结合的化合物）表现出相似的生物学活性。孕激素对MCF7乳腺癌细胞系的作用表明，在非常高的浓度下使用这些化合物可能是不利的，但不支持它们在口服避孕药使用者血清中达到的低孕激素浓度下直接刺激乳腺肿瘤增殖中起作用。
