Chen Yongqiang, Wang Ruobing, Huang Shujun, Henson Elizabeth S, Bi Jayce, Gibson Spencer B
Research Institute in Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
Rady Faculty of Health Sciences, College of Pharmacy, University of Manitoba, Winnipeg, MB R3E 0T5, Canada.
Cancers (Basel). 2021 Mar 2;13(5):1038. doi: 10.3390/cancers13051038.
The epidermal growth factor receptor (EGFR) family member erb-b2 receptor tyrosine kinase 2 () is overexpressed in many types of cancers leading to (radio- and chemotherapy) treatment resistance, whereas the underlying mechanisms are still unclear. Autophagy is known to contribute to cancer treatment resistance. In this study, we demonstrate that ERBB2 increases the expression of different autophagy genes including (autophagy-related 12) and promotes ATG12-dependent autophagy. We clarify that lapatinib, a dual inhibitor for EGFR and ERBB2, promoted autophagy in cells expressing only EGFR but inhibited autophagy in cells expressing only ERBB2. Furthermore, breast cancer database analysis of 35 genes in the canonical autophagy pathway shows that the upregulation of and is associated with a low relapse-free survival probability of patients with ERBB2-positive breast tumors following treatments. Downregulation of ERBB2 or ATG12 increased cell death induced by chemotherapy drugs in ERBB2-positive breast cancer cells, whereas upregulation of ERBB2 or ATG12 decreased the cell death in ERBB2-negative breast cancer cells. Finally, ERBB2 antibody treatment led to reduced expression of ATG12 and autophagy inhibition increasing drug or starvation-induced cell death in ERBB2-positive breast cancer cells. Taken together, this study provides a novel approach for the treatment of ERBB2-positive breast cancer by targeting ATG12-dependent autophagy.
表皮生长因子受体（EGFR）家族成员erb-b2受体酪氨酸激酶2（ERBB2）在多种癌症中过度表达，导致（放疗和化疗）治疗耐药，但其潜在机制仍不清楚。已知自噬会导致癌症治疗耐药。在本研究中，我们证明ERBB2会增加包括自噬相关蛋白12（ATG12）在内的不同自噬基因的表达，并促进ATG12依赖性自噬。我们阐明，拉帕替尼作为一种EGFR和ERBB2的双重抑制剂，在仅表达EGFR的细胞中促进自噬，但在仅表达ERBB2的细胞中抑制自噬。此外，对经典自噬途径中35个基因的乳腺癌数据库分析表明，ATG12和其他基因的上调与ERBB2阳性乳腺肿瘤患者治疗后无复发生存概率低相关。ERBB2或ATG12的下调增加了ERBB2阳性乳腺癌细胞中化疗药物诱导的细胞死亡，而ERBB2或ATG12的上调则降低了ERBB2阴性乳腺癌细胞中的细胞死亡。最后，ERBB2抗体治疗导致ATG12表达降低和自噬抑制，增加了ERBB2阳性乳腺癌细胞中药物或饥饿诱导的细胞死亡。综上所述，本研究提供了一种通过靶向ATG12依赖性自噬治疗ERBB2阳性乳腺癌的新方法。
