Wilder James L, Shajahan Shahin, Khattar Nada H, Wilder Dawn M, Yin Jianming, Rushing Rodney S, Beaven Rick, Kaetzel Charlotte, Ueland Frederick R, van Nagell John R, Kryscio Richard J, Lele Subodh M
Division of Gynecologic Oncology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Gynecol Oncol. 2004 Feb;92(2):553-8. doi: 10.1016/j.ygyno.2003.10.040.
Expression analysis of estrogen receptor-beta (ER-beta) and estrogen receptor-alpha (ER-alpha) in tamoxifen-associated malignant endometrial tumors (TAMET) has not previously been published. Antiestrogens complexed with ER-beta have been reported to result in activation of the activator protein-1 (AP-1) pathway that may result in cell proliferation and tumor growth. In this study, the pathologic features and expression of ER-alpha, ER-beta and progesterone receptor (PR) in TAMET were determined and compared to matched cases of non-tamoxifen-associated endometrial cancers.
TAMET (n = 33) were evaluated for pathologic features (tumor type, grade, depth of myometrial invasion, lymphvascular space invasion and lymph node status), expression of ER-alpha, ER-beta and PR, and survival data (mean follow-up: 28.7 months). Each case was matched to two control patients with spontaneous endometrial cancers according to tumor type, grade and stage as well as patient age and weight (mean follow-up: 51.5 months). Formalin-fixed paraffin-embedded tissue sections were immunostained with anti-ER-alpha (1D5, Dako, Carpinteria, CA) and anti-PR (PgR636, Dako). Expression scores were determined as a sum of the product of staining intensity and proportion of cells staining (H-score). Deparaffinized sections of tumor were microdissected followed by RNA isolation. Quantification of ER-beta mRNA was performed by real-time quantitative RT-PCR with results expressed as a percentage of beta-actin mRNA.
Of the 33 cases 20 were endometrioid (8 grade 1, 10 grade 2, 2 grade 3), 9 papillary serous and 4 malignant mullerian mixed tumors. Using a multivariate conditional regression model, TAMET had lower ER-alpha expression (P = 0.018), higher PR expression (P = 0.029), and more frequent expression of ER-beta (P = 0.032) as compared to control cases. Cases with TAMET had more deaths from cancer and significantly worse survival from disease than controls (P = 0.01 by a log rank test).
TAMET are characterized by a lower expression of ER-alpha, higher expression of PR and more frequent expression of ER-beta as compared to spontaneous tumors. Differential expression of ER-alpha and ER-beta may alter the expression of key target genes (such as those induced by AP-1-dependent gene transcription), and contribute to the pathogenesis and clinical behavior of these tumors. Survival from disease was significantly worse for cases with TAMET as compared to controls.
此前尚未发表过关于他莫昔芬相关的恶性子宫内膜肿瘤（TAMET）中雌激素受体-β（ER-β）和雌激素受体-α（ER-α）的表达分析。据报道，与ER-β复合的抗雌激素会导致激活蛋白-1（AP-1）途径的激活，这可能导致细胞增殖和肿瘤生长。在本研究中，确定了TAMET中ER-α、ER-β和孕激素受体（PR）的病理特征和表达情况，并与非他莫昔芬相关子宫内膜癌的匹配病例进行比较。
对33例TAMET进行病理特征（肿瘤类型、分级、肌层浸润深度、淋巴管间隙浸润和淋巴结状态）、ER-α、ER-β和PR表达以及生存数据（平均随访时间：28.7个月）的评估。根据肿瘤类型、分级、分期以及患者年龄和体重，将每例病例与两名患有自发性子宫内膜癌的对照患者进行匹配（平均随访时间：51.5个月）。用抗ER-α（1D5，Dako，加利福尼亚州卡平特里亚）和抗PR（PgR636，Dako）对福尔马林固定石蜡包埋组织切片进行免疫染色。表达评分通过染色强度与染色细胞比例的乘积之和（H评分）来确定。对肿瘤的脱石蜡切片进行显微切割，然后进行RNA分离。通过实时定量逆转录聚合酶链反应对ER-β mRNA进行定量，结果以β-肌动蛋白mRNA的百分比表示。
33例病例中，20例为子宫内膜样癌（8例1级，10例2级，2例3级），9例为乳头状浆液性癌，4例为恶性苗勒管混合瘤。使用多变量条件回归模型，与对照病例相比，TAMET的ER-α表达较低（P = 0.018），PR表达较高（P = 0.029），ER-β表达更频繁（P = 0.032）。TAMET病例的癌症死亡人数更多，疾病生存率明显低于对照组（对数秩检验P = 0.01）。
与自发性肿瘤相比，TAMET的特征是ER-α表达较低，PR表达较高，ER-β表达更频繁。ER-α和ER-β的差异表达可能会改变关键靶基因的表达（如那些由AP-1依赖性基因转录诱导的基因），并有助于这些肿瘤的发病机制和临床行为。与对照组相比，TAMET病例的疾病生存率明显更差。
