Experimental Pathology, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, Sweden ; Surgery, Department of Clinical Sciences Malmö, Lund University, Skåne University Hospital, Malmö, Sweden.
PLoS One. 2013 Aug 22;8(8):e70890. doi: 10.1371/journal.pone.0070890. eCollection 2013.
Wnt-5a protein expression in primary tumors from unselected breast cancer patients has revealed a tumor suppressive function of the protein. However, in vitro experiments on human breast cancer cells have reported contradictory results, indicating both a tumor suppressive and promoting functions of Wnt-5a. This could be due to various functions of Wnt-5a in different subgroups of patients. The unselected cohorts analyzed to date for Wnt-5a protein expression contained few premenopausal patients. The aim of the present investigation was to evaluate the prognostic significance of Wnt-5a protein expression in a cohort of premenopausal women with comprehensive data on biomarkers, molecular subtypes and long-term outcome. In a randomized trial of adjuvant tamoxifen versus no adjuvant treatment, 564 premenopausal primary breast cancer patients were included. The median follow-up time was 14 years. A tumor tissue array was constructed and 361 samples were evaluated for Wnt-5a reactivity by immunohistochemistry. The primary end-point was recurrence-free survival. Wnt-5a protein expression was reduced or lost in 146/361 of tumors and correlated to younger age, estrogen receptor (ER) negativity and triple-negative phenotype. Wnt-5a was a prognostic factor in the whole cohort (p = 0.003). In patients with ER-positive tumors, Wnt-5a was an independent positive prognostic marker (HR 0.51 95% CI: 0.33-0.78 p = 0.002) and HER2 a negative prognostic marker (HR 2.84 95% CI: 1.51-5.31, p = 0.001) in a Cox multivariate analysis adjusted for standard prognostic markers and tamoxifen treatment. In the ER-negative subset, Wnt-5a added no prognostic information. In a subgroup analysis, Wnt-5a was significantly associated with better prognosis in patients with Luminal A tumors (p = 0.04). Conclusively, our results suggest that loss of Wnt-5a is a valuable prognostic marker in premenopausal breast cancer patients in particular in patients with ER-positive tumors and out-performed conventional prognostic factors in this subset of patients.
在未选择的乳腺癌患者的原发性肿瘤中，Wnt-5a 蛋白的表达揭示了该蛋白的肿瘤抑制功能。然而，在人类乳腺癌细胞的体外实验中，报告了相反的结果，表明 Wnt-5a 既具有肿瘤抑制作用，也具有促进作用。这可能是由于 Wnt-5a 在不同患者亚组中的各种功能所致。迄今为止，分析的未选择队列中，Wnt-5a 蛋白表达的绝经前患者很少。本研究的目的是评估 Wnt-5a 蛋白表达在一组具有全面生物标志物、分子亚型和长期结局数据的绝经前妇女中的预后意义。在一项辅助他莫昔芬与无辅助治疗的随机试验中，纳入了 564 例绝经前原发性乳腺癌患者。中位随访时间为 14 年。构建了肿瘤组织微阵列，并通过免疫组织化学评估了 361 个样本的 Wnt-5a 反应性。主要终点是无复发生存率。在 361 个肿瘤样本中，有 146 个肿瘤的 Wnt-5a 蛋白表达减少或缺失，与年龄较小、雌激素受体（ER）阴性和三阴性表型相关。Wnt-5a 在整个队列中是一个预后因素（p=0.003）。在 ER 阳性肿瘤患者中，Wnt-5a 是一个独立的阳性预后标志物（HR 0.51，95%CI：0.33-0.78，p=0.002），而 HER2 是一个阴性预后标志物（HR 2.84，95%CI：1.51-5.31，p=0.001），在调整了标准预后标志物和他莫昔芬治疗的 Cox 多变量分析中。在 ER 阴性亚组中，Wnt-5a 没有提供更多的预后信息。在亚组分析中，Wnt-5a 与 Luminal A 肿瘤患者的更好预后显著相关（p=0.04）。总之，我们的结果表明，Wnt-5a 的缺失是绝经前乳腺癌患者，特别是 ER 阳性肿瘤患者的一个有价值的预后标志物，在该患者亚组中优于传统的预后因素。
