Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China.
Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China.
Arch Biochem Biophys. 2018 May 1;645:54-60. doi: 10.1016/j.abb.2018.03.015. Epub 2018 Mar 14.
Breast cancer arises as the most frequent malignancy, and causes the majority of cancer death among females worldwide. Src is a tyrosine kinase identified as the product of the proto-oncogene and is supposed to promote cancer development and metastasis. Src inhibitors are recently developed and have shown efficacy in breast cancer. Increasing evidences suggest that aberrant expression of miRNAs is involved in cancer development and drug resistance. Identifying miRNAs associated with drug resistance may enhance the sensitivity of targeted therapies, including Src inhibitors. In this study, we established a Src inhibitor saracatinib-resistant breast cancer cell line (SK-BR-3/SI) for the first time. Microarray data and qRT-PCR results showed that miR-19b-3p expression was downregulated in saracatinib-resistant cells compared with saracatinib-sensitive cells. Downregulation of miR-19b-3p remarkably increased the IC value of saracatinib, and promoted cell migration. Further studies found that miR-19b-3p reduced PIK3CA expression by directly targeting PIK3CA gene and the resistance of Src inhibitor might be associated with activation of PI3K/Akt pathway after downregulation of miR-19b-3p. Moreover, we demonstrated that PI3K inhibitor LY294002 could reverse saracatinib resistance in saracatinib-resistant cells, which deserved further preclinical and clinical evaluation of dual inhibition of Src and PI3K in breast cancer.
乳腺癌是最常见的恶性肿瘤，也是全球女性癌症死亡的主要原因。Src 是一种酪氨酸激酶，被认为是原癌基因的产物，能够促进癌症的发展和转移。Src 抑制剂是最近开发的，已被证明对乳腺癌有效。越来越多的证据表明，miRNA 的异常表达与癌症的发展和耐药性有关。鉴定与耐药性相关的 miRNA 可能会提高包括 Src 抑制剂在内的靶向治疗的敏感性。在本研究中，我们首次建立了 Src 抑制剂 saracatinib 耐药的乳腺癌细胞系（SK-BR-3/SI）。微阵列数据和 qRT-PCR 结果显示，saracatinib 耐药细胞中 miR-19b-3p 的表达水平低于 saracatinib 敏感细胞。miR-19b-3p 的下调显著增加了 saracatinib 的 IC 值，并促进了细胞迁移。进一步的研究发现，miR-19b-3p 通过直接靶向 PIK3CA 基因降低 PIK3CA 的表达，下调 miR-19b-3p 后可能与 PI3K/Akt 通路的激活有关。此外，我们还证明了 PI3K 抑制剂 LY294002 可以逆转 saracatinib 耐药细胞中的耐药性，这值得进一步在临床前和临床中评估双重抑制 Src 和 PI3K 在乳腺癌中的作用。
