Matsumoto Jun, Ariyoshi Noritaka, Sakakibara Masahiro, Nakanishi Takeo, Okubo Yoshiyuki, Shiina Nobumitsu, Fujisaki Kaoru, Nagashima Takeshi, Nakatani Yukio, Tamai Ikumi, Yamada Harumi, Takeda Hiroshi, Ishii Itsuko
Department of Clinical Pharmacology, Chiba University Graduate School of Pharmaceutical Sciences, Chiba, Japan; Department of Pharmaceutical Sciences, International University of Health and Welfare, Tochigi, Japan.
Department of Clinical Pharmacology, Chiba University Graduate School of Pharmaceutical Sciences, Chiba, Japan; Division of Pharmacy, Chiba University Hospital, Chiba, Japan.
Drug Metab Pharmacokinet. 2015 Apr;30(2):133-41. doi: 10.1016/j.dmpk.2014.10.005. Epub 2014 Nov 14.
Estrone-3-sulfate (E1S) is thought to be a major estrogen precursor in estrogen receptor (ER)-positive breast cancer. Since E1S is a hydrophilic compound, the uptake of E1S into cancer cells is probably mediated by transporters, such as organic anion-transporting polypeptide (OATP, SLCO) family. In this study, we investigated the relationship between expression of OATP2B1 and cell proliferation in ER-positive breast cancer. Cell-based assays were carried out in MCF-7 cells both with and without overexpression of OATP2B1. Normal breast and tumor tissues were collected and used in this study. Cell proliferation, ER-mediated transcriptional activities and estradiol secretion were stimulated by addition of E1S to the culture medium of MCF-7 cells. These stimulatory effects were significantly greater in MCF-7 cells overexpressing OATP2B1 than in control cells. The expression level of SLCO2B1 mRNA was significantly correlated with histological grade, Ki-67 labelling index and mRNA expression of steroid sulfatase. The expression level of SLCO2B1 mRNA in luminal B-like cancers was higher than that in luminal A-like cancers. Uptake of E1S resulted in down-regulation of ERα protein and induction of Ki-67 in MCF-7 cells. The present study suggests that OATP2B1 is involved in cell proliferation by increasing the amount of estrogen in ER-positive breast cancer cells.
硫酸雌酮（E1S）被认为是雌激素受体（ER）阳性乳腺癌中的主要雌激素前体。由于E1S是一种亲水性化合物，E1S进入癌细胞的过程可能由转运蛋白介导，如有机阴离子转运多肽（OATP，SLCO）家族。在本研究中，我们调查了OATP2B1的表达与ER阳性乳腺癌细胞增殖之间的关系。在有和没有过表达OATP2B1的MCF-7细胞中进行了基于细胞的实验。本研究收集并使用了正常乳腺组织和肿瘤组织。通过向MCF-7细胞培养基中添加E1S来刺激细胞增殖、ER介导的转录活性和雌二醇分泌。在过表达OATP2B1的MCF-7细胞中，这些刺激作用明显大于对照细胞。SLCO2B1 mRNA的表达水平与组织学分级、Ki-67标记指数和类固醇硫酸酯酶的mRNA表达显著相关。腔面B样癌中SLCO2B1 mRNA的表达水平高于腔面A样癌。E1S的摄取导致MCF-7细胞中ERα蛋白下调和Ki-67诱导。本研究表明，OATP2B1通过增加ER阳性乳腺癌细胞中的雌激素量来参与细胞增殖。
