Flindris Stefanos, Markozannes Georgios, Margioula-Siarkou Chrysoula, Tsiaras Nikolaos, Margioula-Siarkou Georgia, Chalitsios Christos, Sakellariou Eleni, Flindris Konstantinos, Styliara Effrosyni, Paschopoulos Minas, Petousis Stamatios, Navrozoglou Iordanis, Dinas Konstantinos
Department of Obstetrics and Gynecology, University Hospital of Ioannina, University of Ioannina, Ioannina, Greece.
2nd Department of Obstetrics and Gynecology, General Hospital of Thessaloniki "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece.
Cancer Diagn Progn. 2025 Jun 30;5(4):515-529. doi: 10.21873/cdp.10466. eCollection 2025 Jul-Aug.
BACKGROUND/AIM: This study evaluated the immunohistochemical expression of IRE1 and PERK in breast cancer and explored their associations with clinicopathologic characteristics and survival outcomes.
A cohort of 72 breast cancer specimens and 16 controls was analyzed for IRE1 and PERK expression using immunohistochemistry. Associations with clinicopathological variables, hormone receptor status, tumor markers and survival outcomes were assessed using statistical analyses, including Kaplan-Meier survival curves and Cox proportional hazard models.
IRE1 and PERK expression levels were significantly elevated in breast cancer tissues compared to controls (<0.001). Strong positive correlation was observed between IRE1 and PERK expression (Spearman's ρ=0.55, <0.001). High PERK expression was associated with older age (=0.038) and tumor grade 3 (=0.042), while high IRE1 expression correlated with advanced TNM stage (<0.001), estrogen receptor (=0.031), progesterone receptor (=0.028), and human epidermal growth factor receptor 2 positivity (=0.028), as well as increased Ki-67 index (=0.003), suggesting a more aggressive tumor phenotype. IRE1 expression was significantly associated with sentinel lymph node positivity (=0.001) but inversely related to axillary lymph node involvement (=0.031). Multivariate Cox regression analysis revealed that high IRE1 expression [immunoreactivity score (IRS) 5-12] was linked to an increased mortality risk [hazard ratio (HR)=12.19, 95% confidence interval (CI)=0.99-150.35, =0.05], and high PERK expression (IRS 4-12) was similarly associated with worse survival (HR=12.10, 95%CI=1.16-126.30, =0.04). Tumor stage was the strongest predictor of mortality (HR=79.89, <0.01).
High IRE1 and PERK expression levels are associated with aggressive tumor characteristics and reduced survival in breast cancer, underscoring the importance of the unfolded protein response in carcinogenesis and disease progression.
背景/目的：本研究评估了IRE1和PERK在乳腺癌中的免疫组化表达，并探讨了它们与临床病理特征及生存结果的相关性。
采用免疫组化法分析了72例乳腺癌标本及16例对照中IRE1和PERK的表达。使用包括Kaplan-Meier生存曲线和Cox比例风险模型在内的统计分析方法评估其与临床病理变量、激素受体状态、肿瘤标志物及生存结果的相关性。
与对照组相比，乳腺癌组织中IRE1和PERK的表达水平显著升高（<0.001）。IRE1与PERK的表达之间存在强正相关（Spearman氏ρ=0.55，<0.001）。高PERK表达与年龄较大（=0.038）及肿瘤3级（=0.042）相关，而高IRE1表达与TNM晚期（<0.001）、雌激素受体（=0.031）、孕激素受体（=0.028）及人表皮生长因子受体2阳性（=0.028）相关，同时Ki-67指数升高（=0.003），提示肿瘤表型更具侵袭性。IRE1表达与前哨淋巴结阳性显著相关（=0.001），但与腋窝淋巴结受累呈负相关（=0.031）。多因素Cox回归分析显示，高IRE1表达[免疫反应评分（IRS）5-12]与死亡风险增加相关[风险比（HR）=12.19，95%置信区间（CI）=0.99-150.35，=0.05]，高PERK表达（IRS 4-12）同样与较差的生存相关（HR=12.10，95%CI=1.16-126.30，=0.04）。肿瘤分期是死亡的最强预测因素（HR=79.89，<0.01）。
高IRE1和PERK表达水平与乳腺癌侵袭性肿瘤特征及生存降低相关，强调了未折叠蛋白反应在致癌作用和疾病进展中的重要性。
