Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer

Lichao Sun, Joseph Burnett, Mari Gasparyan, Fangying Xu, Hui Jiang, Chang Ching Lin, Ila Myers, Hasan Korkaya, Yajing Liu, Jamie Connarn, Huining He, Ning Zhang, Max S. Wicha, Duxin Sun

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Continued use of trastuzumab in PTEN-deficient HER2+ breast cancer induces the epithelial-to-mesenchymal transition (EMT), transforms HER2+ to triple negative breast cancer, and expands breast cancer stem cells (BCSCs). Using cancer cell lines with two distinct states, epithelial and mesenchymal, we identified novel targets during EMT in PTEN-deficient trastuzumab-resistant breast cancer. Differential gene expression and distinct responses to a small molecule in BT474 (HER2+ trastuzumabsensitive) and the PTEN-deficient trastuzumab-resistant derivative (BT474-PTEN-LTT) provided the selection tools to identify targets during EMT. siRNA knockdown and small molecule inhibition confirmed MEOX1 as one of the critical molecular targets to regulate both BCSCs and mesenchymal-like cell proliferation. MEOX1 was associated with poor survival, lymph node metastasis, and stage of breast cancer patients. These findings suggest that MEOX1 is a clinically relevant novel target in BCSCs and mesenchymal-like cancer cells in PTEN-deficient trastuzumab resistant breast cancer and may serve as target for future drug development.

Original languageEnglish (US)
Pages (from-to)51408-51422
Number of pages15
JournalOncotarget
Volume7
Issue number32
DOIs
StatePublished - Aug 1 2016

Keywords

  • Cancer stem cells
  • EMT
  • HER2+ breast cancer
  • MEOX1
  • Trastuzumab resistance

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Sun, L., Burnett, J., Gasparyan, M., Xu, F., Jiang, H., Lin, C. C., Myers, I., Korkaya, H., Liu, Y., Connarn, J., He, H., Zhang, N., Wicha, M. S., & Sun, D. (2016). Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer. Oncotarget, 7(32), 51408-51422. https://doi.org/10.18632/oncotarget.9839