Chen Hsin-An, Chang Yi-Wen, Tseng Chi-Feng, Chiu Ching-Feng, Hong Chih-Chen, Wang Weu, Wang Ming-Yang, Hsiao Michael, Ma Jui-Ti, Chen Chung-Hsing, Jiang Shih-Sheng, Wu Chih-Hsiung, Hung Mien-Chie, Huang Ming-Te, Su Jen-Liang
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
Ann Surg Oncol. 2015 Mar;22(3):889-98. doi: 10.1245/s10434-014-4061-3. Epub 2014 Sep 12.
Triple-negative breast cancer (TNBC) is defined by reduced expression of the estrogen receptor, progesterone receptor, and HER2. TNBC is an especially aggressive group of breast cancers with poor prognosis. There are currently no validated molecular targets to effectively treat this disease. Thus, it is necessary to identify effective molecular targets and therapeutic strategies for TNBC patients.
The expression of HSPA5 in patients with breast cancer was examined by immunohistochemistry. The association of HSPA5 expression with tumor grade and metastatic events in TNBC patients was analyzed using the Oncomine database. The knockdown and overexpression of HSPA5 protein were performed to investigate the effects on E1A-suppressed cell migration/invasion of TNBC using in vitro transwell assays and tumor growth/experimental metastasis studies in animal models.
The expression of HSPA5 was positively correlated with high-grade tumors, metastatic events, and poor overall survival in breast cancer patients with TNBC. E1A-inhibited HSPA5 expression suppressed cell migration/invasive ability of TNBC cell lines. Moreover, E1A significantly abolished lung metastases from breast cancer cells by inhibiting HSPA5 expression in a xenograft tumor model.
The overexpression of HSPA5 is critical for high-risk metastasis of breast cancer and TNBC. The results of our study suggest that HSPA5 may be a crucial mediator of E1A-suppressed metastatic ability of breast cancer cells. Thus, E1A may be a potential target for diagnosis and individualized treatment in clinical practice.
三阴性乳腺癌（TNBC）的定义是雌激素受体、孕激素受体和HER2表达降低。TNBC是一类侵袭性特别强的乳腺癌，预后较差。目前尚无经过验证的有效治疗该疾病的分子靶点。因此，有必要为TNBC患者确定有效的分子靶点和治疗策略。
采用免疫组织化学法检测乳腺癌患者中HSPA5的表达。利用Oncomine数据库分析TNBC患者中HSPA5表达与肿瘤分级和转移事件的相关性。通过体外transwell实验以及动物模型中的肿瘤生长/实验性转移研究，进行HSPA5蛋白的敲低和过表达，以研究其对E1A抑制的TNBC细胞迁移/侵袭的影响。
在TNBC乳腺癌患者中，HSPA5的表达与高级别肿瘤、转移事件及较差的总生存期呈正相关。E1A抑制HSPA5表达可抑制TNBC细胞系的细胞迁移/侵袭能力。此外，在异种移植肿瘤模型中，E1A通过抑制HSPA5表达显著消除了乳腺癌细胞的肺转移。
HSPA5的过表达对乳腺癌和TNBC的高风险转移至关重要。我们的研究结果表明，HSPA5可能是E1A抑制乳腺癌细胞转移能力的关键介质。因此，E1A可能是临床实践中诊断和个体化治疗的潜在靶点。
