Shibuya Rie, Suzuki Takashi, Miki Yasuhiro, Yoshida Kimako, Moriya Takuya, Ono Katsuhiko, Akahira Jun-ichi, Ishida Takanori, Hirakawa Hisashi, Evans Dean B, Sasano Hironobu
Department of Pathology, Tohoku University School of Medicine, Sendai, Japan.
Endocr Relat Cancer. 2008 Mar;15(1):113-24. doi: 10.1677/ERC-07-0092.
It is well known that sex steroids play important roles in the development of invasive ductal carcinoma (IDC) of the human breast. However, biological significance of sex steroids remains largely unclear in ductal carcinoma in situ (DCIS), regarded as a precursor lesion of IDC, which is partly due to the fact that the intratumoral concentration of sex steroids has not been examined in DCIS. Therefore, in this study, we first examined the intratumoral concentrations of estradiol and 5alpha-dihydrotestosterone (DHT) using liquid chromatography/electrospray tandem mass spectrometry in DCIS. Intratumoral concentrations of both estradiol and DHT were threefold higher in DCIS than non-neoplastic breast tissues and estrogen-producing enzymes (aromatase, steroid sulfatase, and 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1)), and androgen-producing enzymes (17betaHSD5 and 5alpha-reductase type 1 (5alphaRed1)) were abundantly expressed in DCIS by real-time PCR and immunohistochemical analyses. The intratumoral concentration of DHT was significantly lower in IDC than DCIS, while the expression of aromatase mRNA in carcinoma cells and intratumoral stromal cells was significantly higher in IDC than those in DCIS. Immunohistochemistry for sex steroid-producing enzymes in DCIS demonstrated that 5alphaRed1 immunoreactivity was positively correlated with Ki-67 labeling index and histological grade and was also associated with an increased risk of recurrence in patients with DCIS examined. Results of our study suggest that intratumoral concentrations of estradiol and DHT are increased in DCIS, which is possibly due to intratumoral production of these steroids. Therefore, estradiol and DHT may play important roles in the development of DCIS of the human breast.
众所周知，性类固醇在人类乳腺浸润性导管癌（IDC）的发展中起着重要作用。然而，性类固醇在导管原位癌（DCIS）中的生物学意义在很大程度上仍不清楚，DCIS被认为是IDC的前体病变，部分原因是尚未在DCIS中检测性类固醇的肿瘤内浓度。因此，在本研究中，我们首先使用液相色谱/电喷雾串联质谱法检测了DCIS中雌二醇和5α-二氢睾酮（DHT）的肿瘤内浓度。DCIS中雌二醇和DHT的肿瘤内浓度均比非肿瘤性乳腺组织高三倍，并且通过实时PCR和免疫组织化学分析发现，雌激素生成酶（芳香化酶、类固醇硫酸酯酶和1型17β-羟基类固醇脱氢酶（17βHSD1））以及雄激素生成酶（17βHSD5和1型5α-还原酶（5αRed1））在DCIS中大量表达。IDC中DHT的肿瘤内浓度明显低于DCIS，而癌细胞和肿瘤内基质细胞中芳香化酶mRNA的表达在IDC中明显高于DCIS。DCIS中性类固醇生成酶的免疫组织化学表明，5αRed1免疫反应性与Ki-67标记指数和组织学分级呈正相关，并且在接受检查的DCIS患者中也与复发风险增加有关。我们的研究结果表明，DCIS中雌二醇和DHT的肿瘤内浓度升高，这可能是由于这些类固醇在肿瘤内生成。因此，雌二醇和DHT可能在人类乳腺DCIS的发展中起重要作用。
