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Treatment-induced cell cycle kinetics dictate tumor response to chemotherapy.

Hallett RM, Huang C, Motazedian A, Auf der Mauer S, Pond GR, Hassell JA, Nordon RE, Draper JS - Oncotarget (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.

ABSTRACT
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.

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Mutp53 is associated with chemotherapy sensitivity in breast cancer patients(A) The p53 signature correctly identifies MUTp53/WTp53 tumors in the training cohort. (B) The p53 signature correctly identifies MUTp53/WTp53 tumors in the validation cohort by t-test analysis (*p < 0.0001). (C) The p53 signature correctly identifies MUTp53/WTp53 tumors in the validation cohort by ROC analysis (*p < 0.0001). (D) The p53 signature is associated with patient response in 5 neoadjuvant cohorts of breast cancer patients (AUC and 95% confidence interval is shown).
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Figure 5: Mutp53 is associated with chemotherapy sensitivity in breast cancer patients(A) The p53 signature correctly identifies MUTp53/WTp53 tumors in the training cohort. (B) The p53 signature correctly identifies MUTp53/WTp53 tumors in the validation cohort by t-test analysis (*p < 0.0001). (C) The p53 signature correctly identifies MUTp53/WTp53 tumors in the validation cohort by ROC analysis (*p < 0.0001). (D) The p53 signature is associated with patient response in 5 neoadjuvant cohorts of breast cancer patients (AUC and 95% confidence interval is shown).

Mentions: Our data described above suggested that a reduction of cell cycle gene expression following therapy is associated with chemotherapy resistance and that this is dependent, at least in part, by activation of functional p53 signaling. Based on this data we hypothesized that intact p53 signaling in human breast cancer patients would likely be associated with chemotherapy resistance. To confirm this hypothesis, we sought to test whether a transcriptional signature of TP53 mutational status was associated with response to neoadjuvant chemotherapy, similar to our observations made with the RS. We first interrogated transcriptional data (GSE3494) of 251 breast tumors for which the mutational status of TP53 was also known [27]. In short, we used PAM and 10-fold cross-validation to identify an 18 probe set signature that was associated with p53 status in patient samples (n = 34, training cohort) comprising a subset of the original GSE3494 cohort (Supplementary Table 7). Expectedly, we found that among training patients, those whose tumor harbored mutant TP53 had significantly higher p53 signature scores than those with WT TP53 (Figure 5A, t-test, *p < 0.0001). Among the remaining patients in the GSE3494 cohort (n = 217, validation cohort) we validated the capacity of the p53 gene signature to predict TP53 status, and found that the p53 signature remained significantly associated with tumor p53 status using both t-tests and receiver operator characteristic (ROC) curve analysis (Figures 5B–5C, t-test, *p < 0.0001, AUC: 0.74, *p < 0.0001). Accordingly, these data suggest that our p53 signature can be used as a surrogate marker of tumor TP53 status, and represents a useful tool to examine TP53 status in additional transcriptional breast tumor datasets.


Treatment-induced cell cycle kinetics dictate tumor response to chemotherapy.

Hallett RM, Huang C, Motazedian A, Auf der Mauer S, Pond GR, Hassell JA, Nordon RE, Draper JS - Oncotarget (2015)

Mutp53 is associated with chemotherapy sensitivity in breast cancer patients(A) The p53 signature correctly identifies MUTp53/WTp53 tumors in the training cohort. (B) The p53 signature correctly identifies MUTp53/WTp53 tumors in the validation cohort by t-test analysis (*p < 0.0001). (C) The p53 signature correctly identifies MUTp53/WTp53 tumors in the validation cohort by ROC analysis (*p < 0.0001). (D) The p53 signature is associated with patient response in 5 neoadjuvant cohorts of breast cancer patients (AUC and 95% confidence interval is shown).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4466668&req=5

Figure 5: Mutp53 is associated with chemotherapy sensitivity in breast cancer patients(A) The p53 signature correctly identifies MUTp53/WTp53 tumors in the training cohort. (B) The p53 signature correctly identifies MUTp53/WTp53 tumors in the validation cohort by t-test analysis (*p < 0.0001). (C) The p53 signature correctly identifies MUTp53/WTp53 tumors in the validation cohort by ROC analysis (*p < 0.0001). (D) The p53 signature is associated with patient response in 5 neoadjuvant cohorts of breast cancer patients (AUC and 95% confidence interval is shown).
Mentions: Our data described above suggested that a reduction of cell cycle gene expression following therapy is associated with chemotherapy resistance and that this is dependent, at least in part, by activation of functional p53 signaling. Based on this data we hypothesized that intact p53 signaling in human breast cancer patients would likely be associated with chemotherapy resistance. To confirm this hypothesis, we sought to test whether a transcriptional signature of TP53 mutational status was associated with response to neoadjuvant chemotherapy, similar to our observations made with the RS. We first interrogated transcriptional data (GSE3494) of 251 breast tumors for which the mutational status of TP53 was also known [27]. In short, we used PAM and 10-fold cross-validation to identify an 18 probe set signature that was associated with p53 status in patient samples (n = 34, training cohort) comprising a subset of the original GSE3494 cohort (Supplementary Table 7). Expectedly, we found that among training patients, those whose tumor harbored mutant TP53 had significantly higher p53 signature scores than those with WT TP53 (Figure 5A, t-test, *p < 0.0001). Among the remaining patients in the GSE3494 cohort (n = 217, validation cohort) we validated the capacity of the p53 gene signature to predict TP53 status, and found that the p53 signature remained significantly associated with tumor p53 status using both t-tests and receiver operator characteristic (ROC) curve analysis (Figures 5B–5C, t-test, *p < 0.0001, AUC: 0.74, *p < 0.0001). Accordingly, these data suggest that our p53 signature can be used as a surrogate marker of tumor TP53 status, and represents a useful tool to examine TP53 status in additional transcriptional breast tumor datasets.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus