Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer.
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.
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.|State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China.
Lichao
L
Sun
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
Joseph
J
Burnett
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
Mari
M
Gasparyan
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
Fangying
F
Xu
Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
Hui
H
Jiang
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
Chang-Ching
CC
Lin
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
Ila
I
Myers
Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA, 30912, USA.
Hasan
H
Korkaya
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
Yajing
Y
Liu
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
Jamie
J
Connarn
College 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.
Huining
H
He
College 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.
Ning
N
Zhang
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
Max S
MS
Wicha
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
Duxin
D
Sun
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000068878:Trastuzumab / Q000627:therapeutic use*
D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; C525671:MEOX1 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000068878:Trastuzumab
EMT; HER2+ breast cancer; MEOX1; cancer stem cells; trastuzumab resistance