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.
Breast Neoplasms/drug therapy , Cell Cycle/drug effects , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Neoplasms/drug therapy , Neoplasms/pathology , Antineoplastic Agents/chemistry , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Female , Flow Cytometry , Gene Expression Profiling , Genes, Reporter , Humans , Immunohistochemistry , MCF-7 Cells , Signal Transduction , Tumor Suppressor Protein p53/metabolism
