The biological,clinical and prognostic implications of p53 transcriptional pathways in breast cancers |
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| Authors: | Tarek M Abdel‐Fatah Desmond G Powe Johnson Agboola Martyna Adamowicz‐Brice Roger W Blamey Maria A Lopez‐Garcia Andrew R Green Jorge S Reis‐Filho Ian O Ellis |
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| Affiliation: | 1. Division of Pathology, School of Molecular Medical Sciences, Nottingham University Hospitals NHS Trust, UK;2. Pathology Department, National Liver Institute, Menoufyia University, Egypt;3. Cellular Pathology Queen's Medical Centre, Nottingham University Hospital's NHS Trust, Nottingham NG7 2UH, UK;4. The Children's Brain Tumour Research Centre, University of Nottingham, UK;5. The Breast Institute, Nottingham University Hospitals NHS Trust, UK;6. The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK |
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| Abstract: | We hypothesized that the functional status of p53 transcriptional pathways, rather than p53 protein expression alone, could accurately discriminate between low‐ and high‐risk breast carcinoma (BC) and inform about individuals' tumour biological behaviour. To test this, we studied a well‐characterized series of 990 BCs with long‐term follow‐up, immunohistochemically profiled for p53, its main regulators and downstream genes. Results were validated in an independent series of patients (n = 245) uniformly treated with adjuvant anthracycline‐based chemotherapy. Eleven p53 transcriptional phenotypes were identified with just two main clinical outcomes. (a) Low risk/good prognosis group (active/partially inactive p53 pathways), defined as p53±/MDM4+/MDM2±/Bcl2±/p21±, p53?/MDM4?/MDM2+/Bcl2+/p21± and p53±/MDM4?/MMD2?/Bcl2+/p21±. These tumours had favourable clinicopathological characteristics, including ER+ and long survival after systemic adjuvant‐therapy (AT). (b) High risk/poor prognosis group (completely inactive p53 pathways), defined as p53±/MDM4? MDM2?/Bcl2?/p21?, p53?/MDM4? MDM2+/Bcl2?/p21? and p53±/MDM4?/MDM2?/Bcl2?/p21+. These tumours were characterized by aggressive clinicopathological characteristics and showed shortened survival when treated with AT. Completely inactive p53 pathways but intact p21 axis p53±/MDM4?/MDM2?/Bcl2?/p21+ had the worst prognosis, particularly patients who received AT. Multivariate Cox regression models, including validated prognostic factors for both test and validation series, revealed that the functional status of p53 transcriptional pathways was an independent prognosticator for BC‐specific survival (HR 2.64 and 4.5, p < 0.001, respectively) and disease‐free survival (HR 1.93 and 2.5, p < 0.001, respectively). In conclusion, p53 functional status determined by assessment of p53 regulatory and downstream targets provides independent prognostic value and may help determine more adequate therapeutic regimens for specific subgroups of breast cancer patients. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
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| Keywords: | breast carcinoma p53 transcriptional pathways prognostic and predictive markers immunohistochemistry MDM4 MDM2 Bcl2 |
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