Wnt/β-catenin信号活化与乳腺癌肿瘤浸润淋巴细胞的相关性及其临床意义
Correlation between Wnt/β-catenin signaling and tumor-infiltrating lymphocytes and the clinical significance in breast cancer

摘要：目的 以β-catenin胞质/胞核聚集作为Wnt/β-catenin通路信号活化的指标，研究乳腺癌Wnt/β-catenin信号异常活化对淋巴细胞浸润的影响及其临床意义。方法 在90例乳腺癌手术标本连续石蜡切片中，应用免疫组化SP法评价乳腺癌β-catenin的异常表达情况，应用HE染色观察肿瘤间质淋巴细胞浸润的密度，分析β-catenin表达与临床病理特征及肿瘤浸润淋巴细胞密度的相关性。结果 β-catenin异常表达与乳腺癌组织学分级(P<0.05)、雌激素受体(P<0.01)及孕激素受体表达(P<0.01)相关，而与患者年龄、肿瘤大小、腋窝淋巴结转移及肿瘤TNM分期无关。与激素受体阳性乳腺癌(Luminal A、B型)相比，β-catenin异常表达病例数在激素受体阴性乳腺癌(HER2过表达型、三阴性型)显著增加(P<0.05)。进一步研究发现，β-catenin异常表达与肿瘤间质浸润淋巴细胞密度呈正相关(P<0.05)。在激素受体阴性乳腺癌中，间质浸润淋巴细胞密度显著高于激素受体阳性乳腺癌。结论 Wnt/β-catenin信号在激素受体阴性乳腺癌中显著异常活化并促淋巴细胞向肿瘤间质浸润，提示Wnt/β-catenin通路参与激素受体阴性乳腺癌肿瘤免疫应答过程，可能成为调控肿瘤淋巴细胞浸润的关键靶点。
ABSTRACT: Objective To study whether intratumoral Wnt/β-catenin signaling can affect lymphocyte infiltration in breast cancer and its clinical significance by taking cytoplasmic/nuclear accumulation of β-catenin as a marker of Wnt/β-catenin pathway activation. Methods Retrospective analysis of 90 primary operable breast cancer specimens was made in this study. The distribution of stromal TILs was assessed by regular H-E staining. And the expression of β-catenin was assessed by immunohistochemical method on consecutive sections. The correlation between tumor β-catenin expression and lymphocyte infiltration was evaluated by statistical analysis. Results Abnormal β-catenin expression was associated with tumor grade (P<0.05), ER expression (P<0.01), and PR expression (P<0.01). However, it had no correlation with patient age, tumor size, axillary lymph node metastasis, or tumor TNM stage. β-catenin expression was significantly upregulated in hormone receptor negative breast cancer subtypes, i.e. HER2-enriched BC and TNBC, compared to hormone receptor positive breast cancer subtypes (luminal A, B)(P<0.05). Furthermore, high levels of stromal TILs were associated with β-catenin overexpression by breast cancer (P<0.05). Higher stromal TILs infiltration was detected in hormone receptor negative breast cancer compared with hormone receptor positive one. Conclusion Wnt/β-catenin signaling is significantly upregulated in hormone receptor negative breast cancer, and promotes lymphocyte infiltration to tumor stroma. Wnt/β-catenin pathway may play a critical role in anti-cancer immunity, particularly in hormone receptor negative breast cancer, and may serve as a potential target for regulating immune infiltrates in breast cancer