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Abstract：
Breast cancer (BC) is the most common cancer in women, with incidence rates increasing globally in recent years. Therefore, it is important to find new molecules with prognostic and therapeutic value to improve therapeutic response and quality of life. The polyunsaturated fatty acids (PUFAs) metabolic pathway participates in various physiological processes, as well as in the development of malignancies. Although aberrancies in the PUFAs metabolic pathway have been implicated in carcinogenesis, the functional and clinical relevance of this pathway has not been well explored in BC. To evaluate the clinical significance of soluble epoxide hydrolase (EPHX2) expression in Mexican patients with BC using tissue microarrays (TMAs) and digital pathology (DP). Immunohistochemical analyses were performed on 11 TMAs with 267 BC samples to quantify this enzyme. Using DP, EPHX2 protein expression was evaluated solely in tumor areas. The association of EPHX2 with overall survival (OS) was detected through bioinformatic analysis in public databases and confirmed in our cohort via Cox regression analysis. Clear nuclear expression of EPHX2 was identified. Receiver operating characteristics (ROC) curves revealed the optimal cutoff point at 2.847062 × 10-3 pixels, with sensitivity of 69.2% and specificity of 67%. Stratification based on this cutoff value showed elevated EPHX2 expression in multiple clinicopathological features, including older age and nuclear grade, human epidermal growth factor receptor 2 (HER2) and triple negative breast cancer (TNBC) subtypes, and recurrence. Kaplan-Meier curves demonstrated how higher nuclear expression of EPHX2 predicts shorter OS. Consistently, multivariate analysis confirmed EPHX2 as an independent predictor of OS, with a hazard ratio (HR) of 3.483 and a 95% confidence interval of 1.804-6.724 (p < 0.001). Our study demonstrates for the first time that nuclear overexpression of EPHX2 is a predictor of poor prognosis in BC patients. The DP approach was instrumental in identifying this significant association. Our study provides valuable insights into the potential clinical utility of EPHX2 as a prognostic biomarker and therapeutic target in BC.
摘要：
乳腺癌（BC）是女性最常见的癌症，近年来全球发病率不断上升。因此,寻找具有预后和治疗价值的新分子对改善治疗反应和生活质量非常重要。多不饱和脂肪酸(PUFAs)代谢途径参与多种生理过程,以及恶性肿瘤的发展。尽管PUFAs代谢途径的异常与致癌作用有关，在BC中尚未很好地探索该途径的功能和临床相关性。使用组织微阵列（TMAs）和数字病理学（DP）评估墨西哥BC患者可溶性环氧化物水解酶（EPHX2）表达的临床意义。对具有267BC样品的11个TMA进行免疫组织化学分析以定量该酶。使用DP，仅在肿瘤区域评估EPHX2蛋白表达。通过公共数据库中的生物信息学分析检测到EPHX2与总生存期（OS）的相关性，并通过Cox回归分析在我们的队列中得到证实。鉴定了EPHX2的清晰核表达。接收器工作特性（ROC）曲线显示最佳截止点在2.847062×10-3像素，敏感性为69.2%，特异性为67%。基于该截止值的分层显示在多个临床病理特征中EPHX2表达升高,包括年龄较大和核级，人表皮生长因子受体2（HER2）和三阴性乳腺癌（TNBC）亚型，和复发。Kaplan-Meier曲线表明EPHX2的较高核表达如何预测较短的OS。始终如一，多变量分析证实EPHX2是OS的独立预测因子，风险比（HR）为3.483，95%置信区间为1.804-6.724（p<0.001）。我们的研究首次表明EPHX2的核过度表达是BC患者预后不良的预测因子。DP方法有助于确定这种重要的关联。我们的研究为EPHX2作为BC的预后生物标志物和治疗靶标的潜在临床应用提供了有价值的见解。
