三阴型乳腺癌上皮→间质转化意外

　　众所周知，上皮→间质转化是肿瘤发生远处转移的重要步骤之一。通常认为，远处转移比例最高的三阴型乳腺癌，上皮→间质转化可能最活跃。

　　2019年1月4日，施普林格·自然旗下《乳腺癌研究与治疗》在线发表荷兰阿姆斯特丹大学、荷兰癌症研究所的研究报告，分析了随访期间发生远处转移患者的乳腺原发肿瘤上皮→间质转化状态。

　　该研究首先检测了151例乳腺癌转移患者乳腺原发肿瘤冰冻标本的mRNA表达谱，随后根据130基因检测定义的上皮→间质转化核心特征，对上皮→间质转化状态进行归类，分析原发肿瘤上皮→间质转化状态与临床病理特征、分子亚型、转移类型、化疗效果、生存结局的相关性。此外，利用免疫组化法，比较不同上皮→间质转化状态和生存结局的上皮→间质转化相关蛋白质（CDH1、CDH2、NAT1、SNAI2、TWIST1、VIM、ZEB1）表达水平。

　　结果，66.2%的原发肿瘤为上皮→间质转化活跃状态。出乎意料的是，分析结果表明，84.6%的管腔A型肿瘤、65.1%的管腔型B肿瘤、55.6%的HER2型肿瘤、仅25%的基底型（三阴型为主）肿瘤为上皮→间质转化活跃状态（P<0.001）。上皮→间质转化状态与转移类型、转移相关生存、总生存之间无显著相关性。同样，原发肿瘤的上皮→间质转化状态与转移化疗效果之间无显著相关性。

　　不过，NAT1、TWIST1的免疫染色与上皮→间质转化状态存在显著相关性（P=0.003、P=0.047）。多因素分析表明，无论肿瘤的雌激素受体状态如何，NAT1、TWIST1的免疫染色与上皮→间质转化状态存在显著相关性（P=0.020、P=0.027）。

　　因此，根据130基因检测定义的上皮→间质转化核心特征，乳腺癌的上皮→间质转化状态与非三阴型肿瘤相关，但是与远处转移类型、转移相关生存、总生存、转移化疗效果无关。对于上皮→间质转化的若干免疫组化可能标志，仅NAT1、TWIST1的表达水平与基因表达上皮→间质转化状态相关。

Breast Cancer Res Treat. 2019 Jan 4.

Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior.

Savci-Heijink CD, Halfwerk H, Hooijer GKJ, Koster J, Horlings HM, Meijer SL, van de Vijver MJ.

Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; The Netherlands Cancer Institute, Amsterdam, The Netherlands.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) has been implicated as an important step in the development of distant metastases. We therefore wished to study EMT status of primary breast carcinomas from patients who during follow-up developed distant metastases.

METHODS: mRNA expression profiles of primary breast carcinoma samples (n=151) from patients who developed metastatic disease were analyzed and EMT status was designated using a previously described EMT-core signature. EMT status of the primary tumor was correlated to clinicopathological characteristics, molecular subtypes, metastasis pattern, chemotherapy response and survival outcomes. In addition, using immunohistochemistry, the expression levels of several proteins implicated in EMT were studied (CDH1, CDH2, NAT1, SNAI2, TWIST1, VIM, and ZEB1) compared with the designated EMT status and survival.

RESULTS: Utilizing the 130-gene-EMT-core signature, 66.2% of the primary tumors in the current study was assessed as EMT-activated. In contrast to our expectations, analyses revealed that 84.6% of Luminal A tumors, 65.1% of Luminal B tumors, and 55.6% of HER2-like had an activated EMT status, compared to only 25% of the basal-type tumors (p<0.001). EMT status was not correlated to the pattern of metastatic disease, metastasis-specific survival, and overall survival. Similarly, there was not a significant association between EMT status of the primary tumor and chemotherapy response in the metastatic setting. Immunostaining for NAT1 and TWIST1 correlated with the EMT status (p 0.003 and p 0.047, respectively). Multivariate analyses showed that NAT1 and TWIST1 staining was significantly associated with EMT status regardless of the estrogen receptor status of the tumors (p values: 0.020 and 0.027, respectively).

CONCLUSIONS: The EMT status of breast cancers, as defined by the presence of a core EMT gene expression signature is associated with non-basal-type tumors, but not with the pattern of distant metastasis. Of several potential immunohistochemical EMT markers, only NAT1 and TWIST1 expression levels were associated with the gene expression-based EMT status.

KEYWORDS: Breast carcinoma Chemoresistance Chemotherapy response

PMID: 30610490

DOI: 10.1007/s10549-018-05089-5