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Tumor Biology

, Volume 36, Issue 2, pp 1115–1127 | Cite as

Axl as a downstream effector of TGF-β1 via PI3K/Akt-PAK1 signaling pathway promotes tumor invasion and chemoresistance in breast carcinoma

  • Yanyan Li
  • Li Jia
  • Chen Liu
  • Yanxin Gong
  • Dongliang Ren
  • Ning Wang
  • Xu Zhang
  • Yongfu Zhao
Research Article

Abstract

The invasion and chemoresistance are crucial causes of morbidity and death for cancer patients. Axl is closely associated with malignant phenotype of breast tumor cells, including invasiveness and metastasis. Both breast cancer cell line and tissue displayed increased expression of Axl, especially in highly metastatic breast cancer. On the contrary, experimental inhibition of Axl or transforming growth factor beta 1 (TGF-β1) by RNAi assay could suppress cell invasion ability and chemoresistance. Moreover, the up-regulation of Axl was induced by TGF-β1, further activated phosphatidylinositol 3-kinase (PI3K)/Akt and PAK1 translocation, and resulted in greater cell motility, invasion, and chemoresistance in vitro and in vivo. After the detection and statistics in human breast cancer specimens, we found that the Axl expression was closely correlated with TGF-β1 level, tumor differentiation, lymph node metastasis, and clinical stage (p < 0.01). Our findings support the possibility that Axl is a significant regulator of invasion and chemosensitivity, and it means by targeting Axl or its related signaling pathways, we can reduce the invasion and chemosensitivity of breast tumor.

Keywords

Axl TGF-β1 PI3K/Akt-PAK1 Breast cancer Invasion Chemosensitivity 

Notes

Acknowledgments

This work was supported by a grant from The National Natural Science Foundation of China director fund (No. 81250025).

Disclosure

All institutional and national guidelines for the care and use of laboratory animals were followed and all procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later revision. Informed consent or substitute for it was obtained from all patients for being included in the study. Additional informed consent was obtained from all patients for which identifying information is included in this article.

Conflicts of interest

None

Supplementary material

13277_2014_2677_Fig6_ESM.gif (126 kb)
Supplemental Fig. 1

PI3K/Akt inhibition modulates the invasive ability and tumorigenicity of MDA-MB-231 cells. a Cells were treated with 20 μM LY294002, then further subjected to Akt and PAK1 analysis in MDA-MB-231 cells and MDA-MB-231 Axl shRNA cells, respectively. The phosphorylation levels of Akt and PAK1 were found to be down-regulated especially in MDA-MB-231 Axl shRNA cells treated with LY294002. b After MDA-MB-231 cells been treated with 20 μM Akt shRNA (T308A/S473A) for 48 h, we found that the protein levels of p-Akt and p-PAK1 had a tendency to descend. c SY294002 or Akt shRNA treatment decreased the invasive ability of MDA-MB-231 cells by ECMatrix gel analysis. d Chemoresistance of MDA-MB-231 cells treated with SY294002 or Akt shRNA were evaluated by the value of IC50 in vitro and in vivo. e The average tumor weight in different mice groups was weighted after injecting LY294002 or Akt shRNA in mice with or without 5-FU treatment (p < 0.05). *,# Indicate a significant difference compared with the control. Data are the means ± SD of triplicate determinants (GIF 126 kb)

13277_2014_2677_MOESM1_ESM.tif (1.7 mb)
High resolution image (TIFF 1689 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Yanyan Li
    • 1
  • Li Jia
    • 2
  • Chen Liu
    • 3
  • Yanxin Gong
    • 1
  • Dongliang Ren
    • 1
  • Ning Wang
    • 2
  • Xu Zhang
    • 2
  • Yongfu Zhao
    • 3
  1. 1.Department of General SurgeryThe Second Affiliated Hospital of Dalian Medical UniversityDalianChina
  2. 2.College of Laboratory MedicineDalian Medical UniversityDalianChina
  3. 3.Department of General SurgeryThe Second Affiliated Hospital of Dalian Medical UniversityDalianChina

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