Reimer Francesca, Bryan Sarah, Legler Karen, Karn Thomas, Eppenberger-Castori Serenella, Matschke Jakob, Pereira-Veiga Thais, Wikman Harriet, Witzel Isabell, Müller Volkmar, Schmalfeldt Barbara, Milde-Langosch Karin, Schumacher Udo, Stürken Christine, Oliveira-Ferrer Leticia
Department of Gynaecology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
Goethe University, Frankfurt, Germany.
Cancer Cell Int. 2023 Mar 16;23(1):47. doi: 10.1186/s12935-023-02896-9.
The disruption of epithelial features represents a critical step during breast cancer spread. In this context, the dysregulation of desmosomal proteins has been associated with malignant progression and metastasis formation. Curiously, both tumour suppressive and pro-metastatic roles have been attributed to desmosomal structures in different cancer entities. In the present study, we describe the pro-metastatic role of the desmosomal protein desmocollin 2 (DSC2) in breast cancer.
We analysed the prognostic role of DSC2 at mRNA and protein level using microarray data, western blot analysis and immunohistochemistry. Functional consequences of DSC2 overexpression and DSC2 knock down were investigated in the triple negative breast cancer (TNBC) cell line MDA-MB-231 and its brain-seeking subline MDA-MB-231-BR, respectively in vitro and in vivo.
We found a significantly higher DSC2 expression in the more aggressive molecular subtypes HER2-positive and TNBC than in luminal breast cancers, as well as a significant correlation between increased DSC2 expression and a shorter disease-free-also in multivariate analysis-and overall survival. Additionally, a significant association between DSC2 expression in the primary tumour and an increased frequency of cerebral and lung metastasis could be observed. In vitro, ectopic DSC2 expression or DSC2 down-regulation in MDA-MB-231 and MDA-MB-231-BR led to a significant tumour cell aggregation increase and decrease, respectively. Furthermore, tumour cells displaying higher DSC2 levels showed increased chemoresistance in 3D structures, but not 2D monolayer structures, suggesting the importance of cell aggregation as a means for reduced drug diffusion. In an in vivo brain dissemination xenograft mouse model, reduced expression of DSC2 in the brain-seeking TNBC cells led to a decreased amount of circulating tumour cells/clusters and, in turn, to fewer and smaller brain metastatic lesions.
We conclude that high DSC2 expression in primary TNBC is associated with a poorer prognosis, firstly by increasing tumour cell aggregation, secondly by reducing the diffusion and effectiveness of chemotherapeutic agents, and, lastly, by promoting the circulation and survival of tumour cell clusters, each of which facilitates distant organ colonisation.
上皮特征的破坏是乳腺癌扩散过程中的关键步骤。在此背景下，桥粒蛋白的失调与恶性进展和转移形成有关。奇怪的是，在不同的癌症实体中，桥粒结构既具有肿瘤抑制作用又具有促转移作用。在本研究中，我们描述了桥粒蛋白桥粒芯胶蛋白2（DSC2）在乳腺癌中的促转移作用。
我们使用微阵列数据、蛋白质免疫印迹分析和免疫组织化学分析了DSC2在mRNA和蛋白质水平的预后作用。分别在体外和体内研究了DSC2过表达和敲低在三阴性乳腺癌（TNBC）细胞系MDA-MB-231及其脑转移亚系MDA-MB-231-BR中的功能后果。
我们发现，在侵袭性更强的分子亚型HER2阳性和TNBC中，DSC2的表达明显高于管腔型乳腺癌，并且在多变量分析中，DSC2表达增加与无病生存期缩短和总生存期缩短之间存在显著相关性。此外，在原发性肿瘤中观察到DSC2表达与脑转移和肺转移频率增加之间存在显著关联。在体外，MDA-MB-231和MDA-MB-231-BR中异位表达DSC2或下调DSC2分别导致肿瘤细胞聚集显著增加和减少。此外，显示较高DSC2水平的肿瘤细胞在三维结构中表现出更高的化疗耐药性，但在二维单层结构中则不然，这表明细胞聚集作为减少药物扩散的一种方式的重要性。在体内脑转移异种移植小鼠模型中，在脑转移TNBC细胞中降低DSC2的表达导致循环肿瘤细胞/肿瘤细胞簇数量减少，进而导致脑转移瘤的数量和大小减少。
我们得出结论，原发性TNBC中高表达的DSC2与较差的预后相关，首先是通过增加肿瘤细胞聚集，其次是通过减少化疗药物的扩散和有效性，最后是通过促进肿瘤细胞簇的循环和存活，每一个因素都有助于远处器官的定植。
