BACKGROUND Experimental and epidemiological studies demonstrate a role for 27-hydroxycholesterol (27HC) in breast cancer development, though results are conflicting. Cholesterol 27-hydroxylase (CYP27A1) and oxysterol 7-alpha-hydroxylase (CYP7B1) regulate 27HC concentrations, while differential expression of the liver X receptor (LXR) and estrogen receptor beta (ERβ) may impact the association between 27HC and breast cancer risk. METHODS We evaluated correlates of tumor tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ and the association between circulating prediagnostic 27HC concentrations and breast cancer risk by marker expression in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort including 287 breast cancer cases with tumor tissue available. Tumor protein expression was evaluated using immunohistochemistry, and serum 27HC concentrations quantified using liquid chromatography-mass spectrometry. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS A higher proportion of CYP7B1-positive cases were progesterone receptor (PR)-positive, relative to CYP7B1-negative cases, whereas a higher proportion of ERβ-positive cases were Bcl-2 low, relative to ERβ-negative cases. No differences in tumor tissue marker positivity were observed by reproductive and lifestyle factors. We observed limited evidence of heterogeneity in associations between circulating 27HC and breast cancer risk by tumor tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ, with the exception of statistically significant heterogeneity by LXR-β status in the subgroup of women perimenopausal at blood collection (p = 0.02). CONCLUSION This exploratory study suggests limited associations between tumor marker status and epidemiologic or breast cancer characteristics. Furthermore, the association between circulating 27HC and breast cancer risk may not vary by tumor expression of CYP27A1, CYP7B1, LXR-β, or ERβ.

中文翻译：

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CYP27A1，CYP7B1，LXR-β和ERβ的循环27-羟基胆固醇和乳腺癌组织表达：来自EPIC-Heidelberg队列的结果。

背景实验和流行病学研究证明了27-羟基胆固醇（27HC）在乳腺癌发展中的作用，尽管结果相互矛盾。胆固醇27-羟化酶（CYP27A1）和羟固醇7-α-羟化酶（CYP7B1）调节27HC浓度，而肝X受体（LXR）和雌激素受体β（ERβ）的差异表达可能影响27HC与乳腺癌风险之间的关联。方法在欧洲癌症与营养学前瞻性调查中，通过嵌套的病例对照研究，通过标记物表达评估了CYP27A1，CYP7B1，LXR-β和ERβ与肿瘤组织表达的相关性以及循环前诊断27HC浓度与乳腺癌风险之间的相关性。 （EPIC）-海德堡队列研究包括287例具有肿瘤组织的乳腺癌病例。使用免疫组织化学评估肿瘤蛋白的表达，并使用液相色谱-质谱法对血清27HC浓度进行定量。条件对数回归模型用于估计比值比（OR）和95％置信区间（CI）。结果相对于CYP7B1阴性病例，CYP7B1阳性病例中孕酮受体（PR）阳性的比例更高，而相对于ERβ阴性病例，较高的ERβ阳性病例的Bcl-2低水平。生殖和生活方式因素未观察到肿瘤组织标志物阳性的差异。我们观察到有限的证据表明，通过肿瘤组织中CYP27A1，CYP7B1，LXR-β和ERβ的表达，循环27HC与乳腺癌风险之间存在异质性，除了在采血时围绝经期的女性亚组中LXR-β状态在统计学上具有显着异质性（p = 0.02）。结论这项探索性研究表明肿瘤标志物状态与流行病学或乳腺癌特征之间的关联有限。此外，循环27HC与乳腺癌风险之间的关联可能不会因CYP27A1，CYP7B1，LXR-β或ERβ的肿瘤表达而改变。