Wang B, Rouzier R, Albarracin C T, Sahin A, Wagner P, Yang Y, Smith T L, Meric-Bernstam F, Marcelo Aldaz C, Hortobagyi G N, Pusztai L
Department of Breast Medical Oncology, The University of Texas MD, Anderson Cancer Center, TX 77030-4009, USA.
Breast Cancer Res Treat. 2004 Oct;87(3):205-14. doi: 10.1007/s10549-004-6590-0.
The sigma 1 receptor (S1R) represents a unique drug-binding site that is distinct from any other receptors. We examined S1R expression in human breast cancer and assessed the activity of S1R ligands in breast cancer cell lines. One-hundred nine breast specimens from normal breast, benign breast disease and cancer were examined with immunohistochemistry or RT-PCR and six different cell lines were also evaluated. S1R mRNA overexpression was detected in 64% of breast cancers compared to normal breast tissue. Immunohistochemistry showed positive epithelial cell staining in 60% of invasive and 41% of in situ cancers, 75% of ductal hyperplasia and in 33% of normal breast. The pattern of expression was more diffuse in invasive breast carcinoma compared to other conditions (p = 0.02). S1R expression was neither a prognostic nor a predictive factor for efficacy of adjuvant chemotherapy but the study only included 58 cancer patients and therefore the statistical power is limited. MDA-MB-361, MDA-MB-435, BT20 and MCF7 cells all expressed S1R protein by Western blot. The non-specific S1R ligands haloperidol, reduced haloperidol and progesterone produced a dose-dependent inhibition of the growth at high (>10 microM) concentrations. Reduced haloperidol also showed additive cytotoxic effects when combined with doxorubicin, vinorelbine , paclitaxel and docetaxel in vitro. The S1R-specific ligand, SKF 10047 demonstrated the least growth inhibitory activity and showed no interaction with chemotherapy. These results demonstrate that some normal and most neoplastic breast epithelial cells and cell lines commonly express S1R. High concentrations of haloperidol inhibit the growth of these cells and potentiate the effect of chemotherapy in vitro.
西格玛1受体（S1R）是一个独特的药物结合位点，与其他任何受体都不同。我们检测了人乳腺癌中S1R的表达，并评估了S1R配体在乳腺癌细胞系中的活性。采用免疫组织化学或逆转录聚合酶链反应（RT-PCR）检测了109份来自正常乳腺、乳腺良性疾病和癌症的乳腺标本，同时也评估了6种不同的细胞系。与正常乳腺组织相比，64%的乳腺癌中检测到S1R mRNA过表达。免疫组织化学显示，60%的浸润性癌和41%的原位癌、75%的导管增生以及33%的正常乳腺上皮细胞染色呈阳性。与其他情况相比，浸润性乳腺癌中的表达模式更为弥漫（p = 0.02）。S1R表达既不是辅助化疗疗效的预后因素也不是预测因素，但该研究仅纳入了58例癌症患者，因此统计效力有限。通过蛋白质印迹法，MDA-MB-361、MDA-MB-435、BT20和MCF7细胞均表达S1R蛋白。非特异性S1R配体氟哌啶醇、还原氟哌啶醇和孕酮在高浓度（>10 microM）时产生剂量依赖性的生长抑制作用。在体外，还原氟哌啶醇与多柔比星、长春瑞滨、紫杉醇和多西他赛联合使用时也显示出相加的细胞毒性作用。S1R特异性配体SKF 10047表现出最小的生长抑制活性，且与化疗无相互作用。这些结果表明，一些正常和大多数肿瘤性乳腺上皮细胞及细胞系通常表达S1R。高浓度的氟哌啶醇可抑制这些细胞的生长，并在体外增强化疗效果。
