Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Department of Thoracic Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China.
Cancer Med. 2023 May;12(9):10768-10780. doi: 10.1002/cam4.5768. Epub 2023 Mar 7.
Multidrug resistance (MDR) is a primary limitation of breast cancer chemotherapy. The common mechanism of MDR is various anticancer drugs can be effluxed by the cell membrane protein P-glycoprotein (P-gp). Here, we found that ectopic overexpression of Shc3 was detected specifically in drug-resistant breast cancer cells, consequently reducing sensitivity to chemotherapy and promoting cell migration by mediating P-gp expression. However, the molecular mechanism underlying the interplay between P-gp and Shc3 in breast cancer is unknown. We reported an additional resistance mechanism involving an increase in the active form of P-gp after Shc3 upregulation. MCF-7/ADR and SK-BR-3 cells can be sensitive to doxorubicin after knockdown of Shc3. Our results indicated that the interaction between ErbB2 and EphA2 is indirect and regulated by Shc3, and also, this complex is essential for activation of the MAPK and AKT pathways. Meanwhile, Shc3 promotes ErbB2 nuclear translocation, followed by a subsequent increase of the COX2 expression through ErbB2 binding to the COX2 promoter. We further demonstrated that COX2 expression was positively correlated with P-gp expression and the Shc3/ErbB2/COX2 axis upregulates P-gp activity in vivo. Our results show the crucial roles of Shc3 and ErbB2 in modulating P-gp efficacy in breast cancer cells and suggest that Shc3 inhibition may enhance the sensitivity to chemotherapeutic drugs that target oncogene addiction pathways.
多药耐药（MDR）是乳腺癌化疗的主要限制因素。MDR 的常见机制是各种抗癌药物可被细胞膜蛋白 P-糖蛋白（P-gp）外排。在这里，我们发现 Shc3 的异位过表达在耐药乳腺癌细胞中特异性检测到，从而通过介导 P-gp 表达降低对化疗的敏感性并促进细胞迁移。然而，P-gp 和 Shc3 之间在乳腺癌中的相互作用的分子机制尚不清楚。我们报道了另一种耐药机制，涉及 Shc3 上调后 P-gp 活性形式增加。敲低 Shc3 后，MCF-7/ADR 和 SK-BR-3 细胞对阿霉素敏感。我们的结果表明，ErbB2 和 EphA2 之间的相互作用是间接的，并受 Shc3 调节，并且该复合物对于 MAPK 和 AKT 途径的激活至关重要。同时，Shc3 促进 ErbB2 核易位，随后通过 ErbB2 与 COX2 启动子结合增加 COX2 表达。我们进一步证明 COX2 表达与 P-gp 表达呈正相关，并且 Shc3/ErbB2/COX2 轴在体内上调 P-gp 活性。我们的结果表明 Shc3 和 ErbB2 在调节乳腺癌细胞中 P-gp 功效方面的重要作用，并表明 Shc3 抑制可能增强针对致癌基因成瘾途径的化学治疗药物的敏感性。
