The analysis of intratumoral estrogen metabolism and production in human breast and endometrial carcinoma

我们研究了雌激素依赖性肿瘤中雌激素的代谢和产生及其生物学意义，包括人类子宫内膜癌和乳腺癌。我们首先研究了参与雌酮和雌二醇相互转化的17β-羟基类固醇脱氢酶1和2的活性和表达。在人乳腺癌中，17βHSD1在实际癌组织和乳腺癌细胞系中均占优势，而在人子宫内膜癌中，17βHSD2在实际癌组织(10 2例)及其细胞系中均占优势。这些结果表明，尽管存在雌激素受体，但人类子宫内膜癌和乳腺癌的雌激素代谢和作用是不同的。我们进一步证明了这些酶的表达和活性受维甲酸和黄体酮的调节。这些结果表明，在这些雌激素依赖型肿瘤中，这些激素作为肿瘤内代谢调节剂的重要性。因此，我们随后检测了维甲酸受体(RARαβ和γ，RXRαβ和γ)和孕激素受体A和B在这些肿瘤中的表达。我们证明，这些受体的存在可能在调节人乳腺癌和子宫内膜癌中17βHSD的表达中发挥重要作用。参与肿瘤内雌激素代谢的其他重要酶是雌激素硫酸酯酶(STS)和雌激素硫转移酶(EST)。因此，我们研究了这两种重要的酶在人类乳腺癌中的表达。肿瘤中STS的存在与肿瘤的大小和复发密切相关，但EST的存在对患者的临床预后有积极的影响。EST的存在是影响乳腺癌预后的独立因素。

We have studied intratumoral metabolism and production of estrogens and its biological significance in estrogen dependent neoplasms including human endometrial and breast carcinoma. We first studied the activity and expression of 17β-hydroxysteroid dehydrogenase (HSD) type 1 and 2, involved in the interconversion of estrone and estrodiol. In human breast carcinoma, 17βHSD1 is dominant in both actual carcinoma cases (178 cases) and cell lines derived from breast cancer whereas in human endometrial carcinoma, 17βHSD2 is dominant in both actual carcinoma cases (102 cases) and its cell lines. These results suggest that intratumoral estrogen metabolism and actions is different between human endometrial and breast carcinoma despite the presence of estrogen receptor. We further demonstrated that the expression and activity of these enzymes are regulated by retinoids and progesterones. These results suggest the importance of these as regulators of intratumoral metabolism in these estrogen dependent neoplasms. Therefore, we then examined the expression of retinoid receptors (RAR α β and γ, RXR α β and γ) and progesterone receptors A and B in these tumors. We demonstrated that the presence of these receptors may play important roles in regulation of intratumoral 17β HSDs in human breast and endometrial carcinoma. Other important enzymes involved in intratumoral estrogen metabolism are estrogen sulfatase (STS) and estrogen sulfotransferase (EST). We therefore examined the expression of these two important enzymes in human breast carcinoma. The presence of STS in tumor was significantly associated with large tumor diameters and recurrence but that of EST exerts beneficial effects on the clinical outcome of the patients. The presence of EST turned out to be an independent prognostic factors of breast cancers.