Triple-negative breast cancer: Present challenges and new perspectives

Received 19 January 2010; accepted 16 April 2010. published online 03 May 2010.

Abstract

Triple-negative breast cancers (TNBC), characterized by absence of estrogen receptor (ER), progesterone receptor (PR) and lack of overexpression of human epidermal growth factor receptor 2 (HER2), are typically associated with poor prognosis, due to aggressive tumor phenotype(s), only partial response to chemotherapy and present lack of clinically established targeted therapies. Advances in the design of individualized strategies for treatment of TNBC patients require further elucidation, by combined ‘omics’ approaches, of the molecular mechanisms underlying TNBC phenotypic heterogeneity, and the still poorly understood association of TNBC with BRCA1 mutations. An overview is here presented on TNBC profiling in terms of expression signatures, within the functional genomic breast tumor classification, and ongoing efforts toward identification of new therapy targets and bioimaging markers. Due to the complexity of aberrant molecular patterns involved in expression, pathological progression and biological/clinical heterogeneity, the search for novel TNBC biomarkers and therapy targets requires collection of multi-dimensional data sets, use of robust multivariate data analysis techniques and development of innovative systems biology approaches.

Keywords: Triple-negative breast cancer, Systems biology, BRCA1, BRCA2, Chemotherapy, Targeted therapies

Abbreviations: aCGH, array comparative genomic hybridization, CK, cytokeratin, CI, confidence interval, EGF, epidermal growth factor, EGFR (or HER1), epidermal growth factor receptor, EMT, epithelial–mesenchymal transition, ER, estrogen receptor, HER2 (or Her2/neu, or ErbB2), human epidermal growth factor receptor 2, HMMR, hyaluronan-mediated mobility receptor, HR-MAS, high resolution magic angle spinning, IHC, immunohistochemistry, LC, liquid chromatography, MNI, mode-of-action by network identification, MRI, magnetic resonance imaging, MRS, magnetic resonance spectroscopy, MRSI, magnetic resonance spectroscopic imaging, ODE, ordinary differential equation, PARP, poly(ADP-ribose) polymerase, PCA, principal component analysis, PET, positron emission tomography, PR, progesterone receptor, Rb, retinoblastoma, ROC, receiver operating characteristic, TK, tyrosine kinase, TKI, tyrosine kinase inhibitor, TNBC, triple-negative breast cancer

a Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy

b Institute of Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands

c Department of Biological Regulation, Weizmann Institute of Science, 76100 Rehovot, Israel

d PamGene International BV, Nieuwstraat 30, 5211NL's-Hertogenbosch, The Netherlands

e Theoretical Biophysics, Humboldt-Universität zu Berlin, Invalidenstr. 42, 10115 Berlin, Germany

f Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), MTFS, 7489 Trondheim, Norway

g Department of Electrical Engineering (ESAT), Katholieke Universiteit Leuven, Kasteelpark Arenberg 10, 3001 Leuven, Belgium

h Department of Medical Oncology 452, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands

i Fundacion Investigacion Hospital Clinico de Valencia/INCLIVA, Avda. Blasco Ibañez, 17, 46010 Valencia, Spain

j Biochemistry, NMI Natural and Medical Sciences Institute at the University of Tuebingen, Markwiesenstrasse 55, 72770 Reutlingen, Germany

k Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, N-0310 Oslo, Norway

l Department of Pathology, Oslo University Hospital Radiumhospitalet, Montebello, N-0310 Oslo, Norway

m Biomedical Research Group, Department of Informatics, University of Oslo, PO Box 1080 Blindern, N-0316 Oslo, Norway

n Department of Experimental Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy

Corresponding author. Tel.: +39 06 49902686.

PII: S1574-7891(10)00028-1

doi:10.1016/j.molonc.2010.04.006

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