Pasqualini J R, Chetrite G, Nestour E L
CNRS Steroid Hormone Research Unit, Paris, France.
J Endocrinol. 1996 Sep;150 Suppl:S99-105.
Oestradiol (E2) is one of the most important factors supporting the growth and evolution of breast cancer; consequently, to block this hormone has been one of the main targets in recent years. The evaluation of oestrogens (oestrone, oestradiol and their sulphates) in the breast tissue of post-menopausal patients with breast cancer indicates high levels, particularly of oestrone sulphate (E1S) which is 15-25 times higher than in the plasma. Two main pathways are involved in the formation of oestrogens the sulphatase pathway which transforms E1,S into oestrone (E1), and the aromatase pathway which converts androgens into oestrogens. Comparative studies in breast cancer tissues show that the sulphatase pathway is 50-300 times more important than that of the aromatase pathway. Using intact cells and physiological concentrations of E1S (5 x 10(9)M) the conversion to oestradiol was very intense with the hormone-dependent (T-171). MCF-7) breast cancer cells, but very little or no E2 was obtained with the hormone-independent (MDA-MB-231, MDA-MB-436) cells. However, when the latter cells were homogenized, the oestrone sulphatase became very intense. This contradiction in the comparison of the sulphatase activity of the intact cell and the homogenate of the hormone-independent cells can be explained by the presence of inhibitory factors or the absence of positive factor(s) involved in the enzyme activity, which could be related to the evolution of the cancer to hormone-independence. Testing different substances, it was proven that promegestone (R-5020), and danazol, as well as decapeptyl in the presence of heparin, are very active in inhibiting sulphatase activity in hormone-dependent breast cancer cells. Using reverse transcriptase-PCR it was possible to detect the presence of oestrone sulphatase mRNA in different mammary cancer cells. The expression of this mRNA is significantly higher in T-471) and MDA-MB-231 than in the other cell lines. A correlation of this mRNA with the enzymatic activities of oestrone sulphate was observed. The progestagen, R-5020, can significantly decrease the sulphatase mRNA in MCF-7 and T-471) cells. As this progestagen can also inhibit the enzyme itself, it is suggested that the decrease in sulphatase activity by antisulphatase agents in breast cancer cells is a complex mechanism involving not only the effect on the enzyme but also the transcriptional factor(s). It is concluded that in addition to the control of aromatase, specific inhibition of oestrone sulphatase with antisulphatase agents can open new possibilities in breast cancer treatment.
雌二醇（E2）是支持乳腺癌生长和发展的最重要因素之一；因此，阻断这种激素一直是近年来的主要目标之一。对绝经后乳腺癌患者乳腺组织中雌激素（雌酮、雌二醇及其硫酸盐）的评估表明其水平较高，尤其是硫酸雌酮（E1S），其含量比血浆中高15 - 25倍。雌激素的形成涉及两条主要途径，硫酸酯酶途径将E1S转化为雌酮（E1），芳香化酶途径将雄激素转化为雌激素。乳腺癌组织的比较研究表明，硫酸酯酶途径比芳香化酶途径重要50 - 300倍。使用完整细胞和生理浓度的E1S（5×10⁻⁹M），激素依赖性（T - 171、MCF - 7）乳腺癌细胞向雌二醇的转化非常强烈，但激素非依赖性（MDA - MB - 231、MDA - MB - 436）细胞几乎没有或没有产生E2。然而，当将后一种细胞匀浆时，硫酸雌酮酶活性变得非常强烈。完整细胞与激素非依赖性细胞匀浆的硫酸酯酶活性比较中的这种矛盾可以通过存在抑制因子或缺乏参与酶活性的正性因子来解释，这可能与癌症向激素非依赖性的演变有关。通过测试不同物质，已证明炔诺孕酮（R - 5020）、达那唑以及在肝素存在下的十肽促性腺激素释放激素类似物在抑制激素依赖性乳腺癌细胞的硫酸酯酶活性方面非常有效。使用逆转录酶 - PCR可以检测到不同乳腺癌细胞中硫酸雌酮酶mRNA的存在。这种mRNA在T - 471和MDA - MB - 231中的表达明显高于其他细胞系。观察到这种mRNA与硫酸雌酮的酶活性之间存在相关性。孕激素R - 5020可以显著降低MCF - 7和T - 471细胞中的硫酸酯酶mRNA。由于这种孕激素也可以抑制酶本身，因此表明抗硫酸酯酶药物降低乳腺癌细胞中硫酸酯酶活性是一种复杂机制，不仅涉及对酶的作用，还涉及转录因子。结论是，除了控制芳香化酶外，用抗硫酸酯酶药物特异性抑制硫酸雌酮酶可为乳腺癌治疗开辟新的可能性。
