转移相关蛋白在乳腺癌原发灶与复发/转移灶中的表达及意义

目的 研究转移相关蛋白在乳腺癌原发灶与复发/转移灶中的生物表达差异，探讨其临床意义及对患者预后的影响。方法 收集复旦大学附属华山医院2001-2016年接受乳房改良根治术、术后经化疗及内分泌治疗、且发生复发或转移的乳腺癌患者共计31例（随访时间15年）。采用免疫组化方法检测患者原发灶及复发/转移灶肿瘤组织中雌激素受体（estrogen receptor，ER）、孕激素受体（progesterone receptor，PR）、人表皮生长因子受体2（CerbB-2）、增殖细胞核抗原（Ki67）、表皮生长因子受体（epidermal growth factor receptor，EGFR）、黏附分子-细胞外基质金属蛋白酶诱导因子（CD147）、活化的（蛋白）激酶C受体1（receptor of activated C-kinase 1，RAC1）及泛素样含PHD和环指域1（ubiquitin-like，containing PHD and RING finger domains 1，UHRF-1）蛋白的表达水平。分析上述蛋白在乳腺癌原发灶与复发/转移灶中表达的差异性，判断上述蛋白表达高低对患者术后无病生存时间的影响。结果 与原发灶相比，复发/转移灶中RAC1表达显著升高（22.6% vs. 48.4%，χ²=4.509，P=0.034）；且对比发现淋巴结转移患者和原发灶>2 cm的乳腺癌患者RAC1表达显著升高（0 vs. 35.0%，χ²=4.973，P=0.033；14.3% vs. 70.6%，χ²=9.827，P=0.002）。随访截至2016年，31例中5人因肿瘤复发进展死亡，26人存活。ER、PR、CD147高表达者无病生存期长，CerbB-2、Ki67、EGFR、RAC1、UHRF-1高表达者无病生存期短。结论 上述转移相关蛋白直接或间接参与了乳腺癌细胞的分化、增殖和侵袭转移，可以预测乳腺癌的预后。除原发灶外，在复发/转移灶中同时联合检测这些指标可进一步帮助临床医师判断患者的预后、选取适合患者的最佳治疗方案，也为乳腺癌靶向治疗药物提供新的研究方向。

Expression and meaning of related proteins in recurrence/metastasis and primary breast cancer

Objective To investigate discordance of related proteins in metastasis between primary and recurrence/metastasis focuses of breast cancer, and to discuss their clinical significance and value on prognosis. Methods We collected 31 patients with locally recurrence or metastasis admitted in Huashan Hospital of Fudan University from 2001 to 2016 (follow-up was 15 years).All patients were performed modified radical mastectomy treatment on the first visit,and then accepted chemotherapy regiment and endocrine therapy.Immunohistochemistry (IHC) was applied to detect the expressions of estrogen receptor (ER),progesterone receptor (PR),human epidermal growth factor receptor (CerbB-2),proliferating cell nuclear antigen (Ki67),epidermal growth factor receptor (EGFR),extracellular matrix metalloproteinase inducer (CD147),receptor of activated C-kinase 1 (RAC1) and ubiquitin-like,containing PHD and RING finger domains 1(UHRF-1) in primary and recurrence/metastasis lesions.The differential expressions of these proteins were analyzed,and the effect of their expression levels on disease-free survival of patients was also estimated. Results The expression rate of RAC1 in recurrent/metastatic lesions was significantly increased compared with the original lesions (22.6% vs. 48.4%;χ²=4.509,P=0.034).Compared with patients without lymph node metastasis, those with lymph node metastasis showed increased expression rate of RAC1 (0 vs. 35.0%,χ²=4.973,P=0.033).Compared with patients with primary lesions within 2 cm in diameter,those >2 cm lesions showed higher expression rate of RAC1 (14.3% vs.70.6%,χ²=9.827,P=0.002).At the end of the follow-up period in 2016,5 of the 31 patients died due to tumor recurrence and progression, and 26 of them survived. Patients with high ER,PR and CD147 expression had a longer disease-free survival,while those with high CerbB-2,Ki67,EGFR,RAC1,UHRF-1 expression had a shorter disease-free survival. Conclusion Metastasis-related proteins are directly or indirectly involved in the differentiation,proliferation,invasion and metastasis of the tumor cells,thus could predict the prognosis of breast cancer. In addition to the primary lesions,the simultaneous detection of these indicators in recurrence/metastasis can further help clinicians to judge the prognosis and select the best treatment protocols,also may provide new research direction for targeted therapy of breast cancer.