miR-19b-3p inhibits breast cancer cell proliferation and reverses saracatinib-resistance by regulating PI3K/Akt pathway

Arch Biochem Biophys. 2018 May 1;645:54-60. doi: 10.1016/j.abb.2018.03.015. Epub 2018 Mar 14.

Abstract

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 IC50 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.

Keywords: Breast cancer; Drug resistance; PI3K/Akt pathway; Src; miR-19b-3p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzodioxoles / pharmacology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics*
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • MicroRNAs / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Quinazolines / pharmacology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • Benzodioxoles
  • Enzyme Inhibitors
  • MAS1 protein, human
  • MIRN19 microRNA, human
  • MicroRNAs
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Mas
  • Quinazolines
  • saracatinib
  • Proto-Oncogene Proteins c-akt