Oncotarget

Research Papers:

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 and Duxin Sun

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Oncotarget. 2016; 7:51408-51422. https://doi.org/10.18632/oncotarget.9839

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Abstract

Lichao Sun1,2,*, Joseph Burnett1,*, Mari Gasparyan1, Fangying Xu1, Hui Jiang3, Chang-Ching Lin1, Ila Myers1, Hasan Korkaya4, Yajing Liu5, Jamie Connarn1, Huining He6, Ning Zhang6, Max S. Wicha5, Duxin Sun1

1Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA

2State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China

3Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA

4Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA, 30912, USA

5Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA

6College of Pharmacy and Tianjin Cancer Institute and Hospital, National Clinical Research Center of Cancer, Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China

*These authors have contributed equally to this work

Correspondence to:

Duxin Sun, email: [email protected]

Keywords: trastuzumab resistance, EMT, cancer stem cells, MEOX1, HER2+ breast cancer

Received: January 11, 2016    Accepted: May 22, 2016    Published: June 06, 2016

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+ trastuzumab-sensitive) 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.


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