title: Interaction between p53 mutation and a somatic HDMX biomarker better defines metastatic potential in breast cancer.
abstract: TP53 gene mutation is associated with poor prognosis in breast cancer, but additional biomarkers that can further refine the impact of the p53 pathway are needed to achieve clinical utility. In this study, we evaluated a role for the HDMX-S/FL ratio as one such biomarker, based on its association with other suppressor mutations that confer worse prognosis in sarcomas, another type of cancer that is surveilled by p53. We found that HDMX-S/FL ratio interacted with p53 mutational status to significantly improve prognostic capability in patients with breast cancer. This biomarker pair offered prognostic utility that was comparable with a microarray-based prognostic assay. Unexpectedly, the utility tracked independently of DNA-damaging treatments and instead with different tumor metastasis potential. Finally, we obtained evidence that this biomarker pair might identify patients who could benefit from anti-HDM2 strategies to impede metastatic progression. Taken together, our work offers a p53 pathway marker, which both refines our understanding of the impact of p53 activity on prognosis and harbors potential utility as a clinical tool.
authors: Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Oxford, United Kingdom.
authors: Anna M
authors: AM
authors: Grawenda
authors: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. KG Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors: Elen K
authors: EK
authors: Møller
authors: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Suzanne
authors: S
authors: Lam
authors: Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Oxford, United Kingdom.
authors: Emmanouela
authors: E
authors: Repapi
authors: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Amina F A S
authors: AF
authors: Teunisse
authors: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors: Grethe I G
authors: GI
authors: Alnæs
authors: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. KG Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors: Anne-Lise
authors: AL
authors: Børresen-Dale
authors: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. KG Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Department of Clinical Molecular Biology (EpiGen), Medical Division, Akershus University Hospital, Lørenskog, Norway.
authors: Vessela N
authors: VN
authors: Kristensen
authors: Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Oxford, United Kingdom.
authors: Colin R
authors: CR
authors: Goding
authors: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Aart G
authors: AG
authors: Jochemsen
authors: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors: Hege
authors: H
authors: Edvardsen
authors: Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Oxford, United Kingdom. gareth.bond@ndm.ox.ac.uk.
authors: Gareth L
authors: GL
authors: Bond
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53