Suzuki Takashi, Miki Yasuhiro, Moriya Takuya, Akahira Jun-ichi, Ishida Takanori, Hirakawa Hisashi, Yamaguchi Yuri, Hayashi Shin-ichi, Sasano Hironobu
Department of Pathology, Tohoku University School of Medicine, Sendai, Japan.
Int J Cancer. 2007 Jan 15;120(2):285-91. doi: 10.1002/ijc.22317.
Previous in vitro studies demonstrated that bioactive androgen 5alpha-dihydrotestosterone (DHT) exerted antiproliferative effects through an interaction with androgen receptor (AR) in breast carcinoma cells. However, AR status has not been examined in association with DHT concentration in breast carcinoma tissues, and significance of androgenic actions remains unclear in breast carcinomas. Therefore, in our study, we first examined intratumoral DHT concentrations in 38 breast carcinoma tissues using liquid chromatography/electrospray tandem mass spectrometry. Intratumoral DHT concentration was positively associated with 5alpha-reductase type 1 (5alphaRed1), and negatively correlated with aromatase. We then examined clinical significance of AR and 5alphaRed1 status in 115 breast carcinoma tissues by immunohistochemistry. Breast carcinomas positive for both AR and 5alphaRed1 were inversely associated with tumor size or Ki-67. These patients showed significant associations with a decreased risk of recurrence and improved prognosis for overall survival, and the AR / 5alphaRed1 status was demonstrated an independent prognostic factor. Moreover, we examined possible regulation of DHT production by aromatase in in vitro studies. DHT synthesis from androstenedione in MCF-7 cells was significantly inhibited by coculture with aromatase-positive stromal cells, which was significantly reversed by addition of aromatase inhibitor exemestane. These results suggest that intratumoral DHT concentration is mainly determined by 5alphaRed1 and aromatase in breast carcinoma tissues, and antiproliferative effect of DHT may primarily occur in the cases positive for both AR and 5alphaRed1. Aromatase inhibitors may be more effective in these patients, possibly due to increasing local DHT concentration with estrogen deprivation.
以往的体外研究表明，生物活性雄激素5α-双氢睾酮（DHT）通过与乳腺癌细胞中的雄激素受体（AR）相互作用发挥抗增殖作用。然而，尚未在乳腺癌组织中结合DHT浓度检测AR状态，雄激素作用在乳腺癌中的意义仍不明确。因此，在我们的研究中，我们首先使用液相色谱/电喷雾串联质谱法检测了38例乳腺癌组织中的瘤内DHT浓度。瘤内DHT浓度与1型5α-还原酶（5αRed1）呈正相关，与芳香化酶呈负相关。然后，我们通过免疫组织化学检测了115例乳腺癌组织中AR和5αRed1状态的临床意义。AR和5αRed1均阳性的乳腺癌与肿瘤大小或Ki-67呈负相关。这些患者显示出复发风险降低和总生存预后改善的显著相关性，并且AR/5αRed1状态被证明是一个独立的预后因素。此外，我们在体外研究中检测了芳香化酶对DHT产生的可能调节作用。与芳香化酶阳性基质细胞共培养可显著抑制MCF-7细胞中雄烯二酮合成DHT，添加芳香化酶抑制剂依西美坦可显著逆转这种抑制作用。这些结果表明，乳腺癌组织中的瘤内DHT浓度主要由5αRed1和芳香化酶决定，DHT的抗增殖作用可能主要发生在AR和5αRed1均阳性的病例中。芳香化酶抑制剂在这些患者中可能更有效，这可能是由于雌激素剥夺导致局部DHT浓度升高。
