Treatment-induced cell cycle kinetics dictate tumor response to chemotherapy.
Chemotherapy fails to provide durable cure for the majority of cancer patients. To identify mechanisms associated with chemotherapy resistance, we identified genes differentially expressed before and after chemotherapeutic treatment of breast cancer patients. Treatment response resulted in either increased or decreased cell cycle gene expression. Tumors in which cell cycle gene expression was increased by chemotherapy were likely to be chemotherapy sensitive, whereas tumors in which cell cycle gene transcripts were decreased by chemotherapy were resistant to these agents. A gene expression signature that predicted these changes proved to be a robust and novel index that predicted the response of patients with breast, ovarian, and colon tumors to chemotherapy. Investigations in tumor cell lines supported these findings, and linked treatment induced cell cycle changes with p53 signaling and G1/G0 arrest. Hence, chemotherapy resistance, which can be predicted based on dynamics in cell cycle gene expression, is associated with TP53 integrity.
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Robin M
RM
Hallett
McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Cheng
C
Huang
McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.|Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Ali
A
Motazedian
Graduate School of Biomedical Engineering, University of New South Wales, Sydney 2052, Australia.
Stefanie
S
Auf der Mauer
Department of Oncology, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Gregory R
GR
Pond
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
John A
JA
Hassell
Graduate School of Biomedical Engineering, University of New South Wales, Sydney 2052, Australia.
Robert E
RE
Nordon
McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Jonathan S
JS
Draper
D000970:Antineoplastic Agents / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
breast cancer; cell cycle; chemotherapy; p53