Expression of membrane transporters and metabolic enzymes involved in estrone-3-sulphate disposition in human breast tumour tissues
Expression of membrane transporters and metabolic enzymes involved in estrone-3-sulphate disposition in human breast tumour tissues
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DOI：
10.1007/s10549-014-2990-y
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发表时间：
2014-06-01
影响因子：
3.8
通讯作者：
Bendayan, Reina
中科院分区：
文献类型：
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作者：
Banerjee, Nilasha;Miller, Naomi;Bendayan, Reina
三分之二新诊断的激素依赖性 (HR+) 乳腺癌是在绝经后患者中检测到的，其中 3-硫酸雌酮 (E3S) 是肿瘤雌二醇的主要来源。了解 E3S 的肿瘤内命运将有助于识别 HR + 绝经后乳腺癌患者的新分子靶点。因此，本研究分别研究了参与 E3S 摄取、流出和代谢的 (i) 有机阴离子转运多肽 (OATP)、(ii) 多药耐药蛋白 (MRP-1)、乳腺癌耐药蛋白 (BCRP) 和 (iii) 硫酸酯酶 (STS)、17 β-羟基类固醇脱氢酶 (17 β-HSD-1) 的临床表达。分别以 4 倍和 20 倍放大倍数获得染色肿瘤切片 (n = 40) 的荧光和明场图像。标记密度测量为阳性信号的总面积除以所分析的肿瘤切片的表面积，并报告为％面积(ImageJ软件)。还对肿瘤、基质和非肿瘤组织面积进行量化（Inform软件），并将每个组织学面积的光强度比报告为%面积/肿瘤、%面积/基质和%面积/非肿瘤。通过在存在或不存在特定抑制剂的情况下进行的转运研究，进一步研究了 OATP 和 STS 在 HR+（MCF-7、T47-D、ZR-75）和 HR-（MDA-MB-231）细胞中的功能作用。在所有转运蛋白和酶中，OATP 和 STS 在 HR+ 肿瘤切片中的表达显着较高 (p < 0.0001)，从组织的肿瘤区域获得的目标信号最高。在所有 HR+ 乳腺癌细胞中也观察到了特定的 OATP 介导的 E3S 摄取和 STS 介导的代谢。这些观察结果表明 OATP 作为 HR+ 乳腺癌新分子靶点的潜力。
Two-thirds of newly diagnosed hormone-dependent (HR+) breast cancers are detected in post-menopausal patients where estrone-3-sulphate (E3S) is the predominant source for tumour estradiol. Understanding intra-tumoral fate of E3S would facilitate in the identification of novel molecular targets for HR + post-menopausal breast cancer patients. Hence this study investigates the clinical expression of (i) organic anion-transporting polypeptides (OATPs), (ii) multidrug resistance protein (MRP-1), breast cancer resistance proteins (BCRP), and (iii) sulphatase (STS), 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD-1), involved in E3S uptake, efflux and metabolism, respectively. Fluorescent and brightfield images of stained tumour sections (n = 40) were acquired at 4x and 20x magnification, respectively. Marker densities were measured as the total area of positive signal divided by the surface area of the tumour section analysed and was reported as % area (ImageJ software). Tumour, stroma and non-tumour tissue areas were also quantified (Inform software), and the ratio of optical intensity per histologic area was reported as % area/tumour, % area/stroma and % area/non-tumour. Functional role of OATPs and STS was further investigated in HR+ (MCF-7, T47-D, ZR-75) and HR-(MDA-MB-231) cells by transport studies conducted in the presence or absence of specific inhibitors. Amongst all the transporters and enzymes, OATPs and STS have significantly (p < 0.0001) higher expression in HR+ tumour sections with highest target signals obtained from the tumour regions of the tissues. Specific OATP-mediated E3S uptake and STS-mediated metabolism were also observed in all HR+ breast cancer cells. These observations suggest the potential of OATPs as novel molecular targets for HR+ breast cancers.