Poulin R, Labrie F
Cancer Res. 1986 Oct;46(10):4933-7.
We have examined the effect of androst-5-ene-3 beta,17 beta-diol (delta 5-diol) and its precursors, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone 3 beta-sulfate (DHEAS), on the growth of the estrogen-sensitive human breast cancer cell line, ZR-75-1. While the cell number was increased up to 4-fold by maximal concentrations of estradiol, delta 5-diol maximally stimulated cell proliferation by approximately 3-fold. Since the half-maximal stimulation achieved by delta 5-diol is observed at 2.5 nM and the normal range of plasma concentrations of this steroid in women is 1 to 3 nM, it is most likely that the stimulatory effect of delta 5-diol has physiological significance. DHEA and DHEAS were much less effective than delta 5-diol in stimulating the proliferation of ZR-75-1 cells, the maximal effect on cell number being 75% at the maximal dose used, namely 10 microM. The mitogenic effects of estradiol and delta 5-diol were competitively inhibited by the antiestrogen LY156758 (keoxifene), while the effects of DHEA and DHEAS were completely abolished by the antiestrogen. The effects of DHEA and delta 5-diol on cell proliferation are not likely to be mediated via their conversion to estrone or estradiol, since androstenedione had no effect, while testosterone and dihydrotestosterone decreased cell number by about 20%. The number of specific progesterone binding sites was increased 3.7-, 3.2-, and 2.0-fold by delta 5-diol, DHEA, and DHEAS, respectively. The relative potency of the C19-delta 5-steroids to increase the number of progesterone-specific binding sites was comparable to their ability to stimulate cell proliferation. Direct competition experiments performed with intact cells in monolayer culture showed that, under conditions of minimal metabolism, only delta 5-diol could significantly compete with estradiol for cellular estrogen-specific binding sites with an apparent dissociation constant of 11 nM, thus suggesting that physiological concentrations of C19-delta 5-steroids of adrenal origin could exert an estrogenic stimulation of breast tumor growth without involvement of the aromatase pathway. The present data suggest not only that estrone derived from androstenedione could play a role in estrogen-sensitive breast cancer in women but that delta 5-diol could well be the most important estrogen in breast cancer in women.
我们研究了雄甾-5-烯-3β,17β-二醇（δ5-二醇）及其前体脱氢表雄酮（DHEA）和脱氢表雄酮3β-硫酸盐（DHEAS）对雌激素敏感的人乳腺癌细胞系ZR-75-1生长的影响。虽然雌二醇的最大浓度可使细胞数量增加至4倍，但δ5-二醇最大可刺激细胞增殖约3倍。由于δ5-二醇在2.5 nM时达到半数最大刺激，且该类固醇在女性血浆中的正常浓度范围为1至3 nM，因此δ5-二醇的刺激作用很可能具有生理意义。DHEA和DHEAS在刺激ZR-75-1细胞增殖方面远不如δ5-二醇有效，在所用最大剂量即10 μM时，对细胞数量的最大影响为75%。雌二醇和δ5-二醇的促有丝分裂作用被抗雌激素LY156758（凯昔芬）竞争性抑制，而DHEA和DHEAS的作用则被抗雌激素完全消除。DHEA和δ5-二醇对细胞增殖的作用不太可能通过它们转化为雌酮或雌二醇来介导，因为雄烯二酮没有作用，而睾酮和二氢睾酮使细胞数量减少约20%。δ5-二醇、DHEA和DHEAS分别使特异性孕酮结合位点的数量增加了3.7倍、3.2倍和2.0倍。C19-δ5-类固醇增加孕酮特异性结合位点数量的相对效力与其刺激细胞增殖的能力相当。在单层培养的完整细胞上进行的直接竞争实验表明，在最低代谢条件下，只有δ5-二醇能以11 nM的表观解离常数与雌二醇竞争细胞雌激素特异性结合位点，因此表明肾上腺来源的C19-δ5-类固醇的生理浓度可在不涉及芳香化酶途径的情况下对乳腺肿瘤生长发挥雌激素刺激作用。目前的数据不仅表明源自雄烯二酮的雌酮可能在女性雌激素敏感的乳腺癌中起作用，而且δ5-二醇很可能是女性乳腺癌中最重要的雌激素。
