Gas6/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt/GSK-3β/β-catenin Signaling

Theranostics. 2016 May 24;6(8):1205-19. doi: 10.7150/thno.15083. eCollection 2016.

Abstract

Chemoresistance in breast cancer has been of great interest in past studies. However, the development of rational therapeutic strategies targeting chemoresistant cells is still a challenge in clinical oncology. By integrating data from global differences of gene expression and phospho-receptor tyrosine kinases between sensitive parental cells (MCF-7) and doxorubicin-resistant cells (MCF-7/ADR), we identified Axl as a potential target for chemoresistance and metastasis in multidrug resistant breast cancer cells. We analyzed Axl expression in 57 breast cancer cell lines and detected a dramatic increase in its expression level in mesenchymal breast cancer cell lines. Axl silencing suppressed invasive and metastatic potentials of chemoresistant breast cancer cells as well as increased elimination of cancer cells when combined with doxorubicin. Furthermore, in preclinical assays, an Axl inhibitor R428 showed increased cell death upon doxorubicin treatment. Additionally, using phospho-kinase array based proteomic analysis, we identified that Akt/GSK-3β/β-catenin cascade was responsible for Axl-induced cell invasion. Nuclear translocation of β-catenin then induced transcriptional upregulation of ZEB1, which in turn regulated DNA damage repair and doxorubicin-resistance in breast cancer cells. Most importantly, Axl was correlated with its downstream targets in tumor samples and was associated with poor prognosis in breast cancer patients. These results demonstrate that Gas6/Axl axis confers aggressiveness in breast cancer and may represent a therapeutic target for chemoresistance and metastasis.

Keywords: Axl; EMT; R428; breast cancer.; drug-resistance.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / metabolism
  • Benzocycloheptenes / administration & dosage
  • Benzocycloheptenes / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Doxorubicin / administration & dosage
  • Doxorubicin / metabolism
  • Drug Resistance*
  • Gene Expression Profiling
  • Gene Silencing
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Heterografts
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Metastasis / pathology*
  • Protein Kinase Inhibitors / metabolism
  • Proto-Oncogene Proteins / biosynthesis*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor Protein-Tyrosine Kinases / biosynthesis*
  • Signal Transduction
  • Treatment Outcome
  • Triazoles / administration & dosage
  • Triazoles / metabolism
  • beta Catenin / metabolism

Substances

  • Antineoplastic Agents
  • Benzocycloheptenes
  • Intercellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Triazoles
  • beta Catenin
  • growth arrest-specific protein 6
  • bemcentinib
  • Doxorubicin
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt