Interaction between p53 mutation and a somatic HDMX biomarker better defines metastatic potential in breast cancer.

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.

[1]  G. Berx,et al.  Regulatory networks defining EMT during cancer initiation and progression , 2013, Nature Reviews Cancer.

[2]  K. Vousden,et al.  p53 mutations in cancer , 2013, Nature Cell Biology.

[3]  Guillermina Lozano,et al.  Molecular Pathways: Targeting Mdm2 and Mdm4 in Cancer Therapy , 2012, Clinical Cancer Research.

[4]  H. Taubert,et al.  Alternate splicing of the p53 inhibitor HDMX offers a superior prognostic biomarker than p53 mutation in human cancer. , 2012, Cancer research.

[5]  Carol Prives,et al.  Mutant p53: one name, many proteins. , 2012, Genes & development.

[6]  David F. Callen,et al.  Mutant p53 uses p63 as a molecular chaperone to alter gene expression and induce a pro-invasive secretome , 2011, Oncotarget.

[7]  L. Pusztai,et al.  Gene expression profiling in breast cancer: classification, prognostication, and prediction , 2011, The Lancet.

[8]  Christopher A. Maher,et al.  A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial–mesenchymal transition , 2011, The Journal of cell biology.

[9]  P. Dijke,et al.  The TGF-β/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system , 2011, Breast Cancer Research and Treatment.

[10]  G. Melino.  p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53 , 2011, Cell Death and Differentiation.

[11]  S. O'toole,et al.  Prediction of outcome of early ER+ breast cancer is improved using a biomarker panel, which includes Ki-67 and p53 , 2011, British Journal of Cancer.

[12]  Israel Steinfeld,et al.  miRNA-mRNA Integrated Analysis Reveals Roles for miRNAs in Primary Breast Tumors , 2011, PloS one.

[13]  Karen H. Vousden,et al.  p53 and its mutants in tumor cell migration and invasion , 2011, The Journal of cell biology.

[14]  Milind B. Suraokar,et al.  TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs , 2010, Nature.

[15]  G. Wahl,et al.  The p53 orchestra: Mdm2 and Mdmx set the tone. , 2010, Trends in cell biology.

[16]  M. Schutte,et al.  Role of Mdm4 in drug sensitivity of breast cancer cells , 2010, Oncogene.

[17]  Ker-Chau Li,et al.  p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug , 2009, Nature Cell Biology.

[18]  W. B. Derry.  Faculty Opinions recommendation of A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. , 2009 .

[19]  A. Nobel,et al.  Supervised risk predictor of breast cancer based on intrinsic subtypes. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  T. Fleming,et al.  Transcriptional repression of epithelial cell adhesion molecule contributes to p53 control of breast cancer invasion. , 2009, Cancer research.

[21]  Alexei Vazquez,et al.  The genetics of the p53 pathway, apoptosis and cancer therapy , 2008, Nature Reviews Drug Discovery.

[22]  T. Iwakuma,et al.  The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. , 2008, Genes & development.

[23]  Eduardo Sontag,et al.  Transcriptional control of human p53-regulated genes , 2008, Nature Reviews Molecular Cell Biology.

[24]  Therese Sørlie,et al.  Presence of bone marrow micrometastasis is associated with different recurrence risk within molecular subtypes of breast cancer , 2007, Molecular oncology.

[25]  M. Olivier,et al.  Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database , 2007, Human mutation.

[26]  Hongjuan Zhao,et al.  TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer , 2007, Breast Cancer Research.

[27]  R. Eeles,et al.  p53 therapy in a patient with Li-Fraumeni syndrome , 2007, Molecular Cancer Therapeutics.

[28]  T. Jacks,et al.  Restoration of p53 function leads to tumour regression in vivo , 2007, Nature.

[29]  Carlos Cordon-Cardo,et al.  Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas , 2007, Nature.

[30]  G. Wahl,et al.  Regulating the p53 pathway: in vitro hypotheses, in vivo veritas , 2006, Nature Reviews Cancer.

[31]  B. Iacopetta,et al.  p53 and disease: when the guardian angel fails , 2006, Cell Death and Differentiation.

[32]  J. Klijn,et al.  Thirteen new p53 gene mutants identified among 41 human breast cancer cell lines , 2006, Breast Cancer Research and Treatment.

[33]  J. Bergh,et al.  The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  L. Vassilev,et al.  In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2 , 2004, Science.

[35]  A. Ciechanover,et al.  HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  K. Helin,et al.  Mdm4 (Mdmx) Regulates p53-Induced Growth Arrest and Neuronal Cell Death during Early Embryonic Mouse Development , 2002, Molecular and Cellular Biology.

[37]  Xin Lu,et al.  Live or let die: the cell's response to p53 , 2002, Nature Reviews Cancer.

[38]  Thierry Soussi,et al.  Assessing TP53 status in human tumours to evaluate clinical outcome , 2001, Nature Reviews Cancer.

[39]  Valerie Reinke,et al.  Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53 , 2001, Nature Genetics.

[40]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[41]  R. Kåresen,et al.  Relationship between abnormal p53 protein and failure to express p21 protein in human breast carcinomas , 1997, The Journal of pathology.

[42]  Lawrence A. Donehower,et al.  Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53 , 1995, Nature.

[43]  Guillermina Lozano,et al.  Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53 , 1995, Nature.

[44]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[45]  L. Strong,et al.  Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. , 1990, Science.

[46]  W. Blattner,et al.  A cancer family syndrome in twenty-four kindreds. , 1988, Cancer research.

[47]  M. Olivier,et al.  p53 in the Clinics , 2013, Springer New York.

[48]  A. Hollestelle,et al.  BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants. , 2006, Cancer research.

[49]  R. Kåresen,et al.  Detection of isolated tumor cells in BM from breast-cancer patients: significance of anterior and posterior iliac crest aspirations and the number of mononuclear cells analyzed. , 2003, Cytotherapy.

[50]  M. Hollstein,et al.  p53 and human cancer: the first ten thousand mutations. , 2000, Advances in cancer research.