Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Cancer Epidemiol Biomarkers Prev. 2010 Jan;19(1):301-9. doi: 10.1158/1055-9965.EPI-09-0741.
Beta-catenin is involved in cell adhesion through catenin-cadherin complexes and as a transcriptional regulator in the Wnt signaling pathway. Its deregulation is important in the genesis of a number of human malignancies, particularly colorectal cancer. A range of studies has been undertaken in breast cancer, with contradictory associations reported among beta-catenin expression, clinicopathologic variables, and disease outcome. We undertook an immunohistochemical study measuring the levels and subcellular localization of beta-catenin in 292 invasive ductal breast cancers with known treatment and outcome. No association with breast cancer-specific death was observed for cytoplasmic or membrane expression alone; however, a continuous score representing both locations (membrane minus cytoplasmic expression: MTC score) was associated with a worse outcome in univariate analysis (P = 0.004), and approached significance in a multivariate analysis model that included lymph node, progesterone receptor (PR), and HER2 status (P = 0.054). Therefore, the MTC score was used for further statistical analyses due to the importance of both the subcellular location and the levels of expression of beta-catenin. An association was identified between high cytoplasmic expression (low MTC score), and high tumor grade (P = 0.004), positive Ki67 (P = 0.005), negative estrogen receptor (ER) (P = 0.005), positive HER2 (P = 0.04) status, and an active phosphoinositide 3-kinase pathway (P = 0.005), measured as PIK3CA mutations (P = 0.05) or PTEN loss (P = 0.05). Low cytoplasmic expression (high MTC score) was associated with the luminal A subtype (P = 0.004). In conclusion, a low beta-catenin MTC score is associated with an adverse outcome in breast cancer, which may be of mechanistic significance in the disease process.
β-连环蛋白通过连接蛋白-钙黏着蛋白复合物参与细胞黏附，并作为 Wnt 信号通路中的转录调节剂。其失调在许多人类恶性肿瘤的发生中很重要，特别是结直肠癌。在乳腺癌中进行了一系列研究，β-连环蛋白表达、临床病理变量和疾病结局之间的关联存在矛盾。我们对 292 例已知治疗和结局的浸润性导管乳腺癌进行了免疫组织化学研究，测量了β-连环蛋白的水平和亚细胞定位。单独的细胞质或膜表达与乳腺癌特异性死亡无关；然而，代表两个位置的连续评分（膜减去细胞质表达：MTC 评分）在单变量分析中与较差的预后相关（P=0.004），并且在包括淋巴结、孕激素受体（PR）和 HER2 状态的多变量分析模型中接近显著（P=0.054）。因此，由于β-连环蛋白的亚细胞定位和表达水平都很重要，因此使用 MTC 评分进行进一步的统计分析。高细胞质表达（低 MTC 评分）与高肿瘤分级（P=0.004）、Ki67 阳性（P=0.005）、雌激素受体（ER）阴性（P=0.005）、HER2 阳性（P=0.04）状态和活性磷脂酰肌醇 3-激酶途径（P=0.005）之间存在关联，这通过 PIK3CA 突变（P=0.05）或 PTEN 缺失（P=0.05）来衡量。低细胞质表达（高 MTC 评分）与腔 A 亚型相关（P=0.004）。总之，β-连环蛋白 MTC 评分低与乳腺癌不良预后相关，这在疾病过程中可能具有机制意义。
