Abstract
Molecular subtypes of breast cancer with relevant biological and clinical features have been defined recently, notably ERBB2-overexpressing, basal-like, and luminal-like subtypes. To investigate the ability of mass spectrometry-based proteomics technologies to analyze the molecular complexity of human breast cancer, we performed a SELDI-TOF MS-based protein profiling of human breast cell lines (BCLs). Triton-soluble proteins from 27 BCLs were incubated with ProteinChip arrays and subjected to SELDI analysis. Unsupervised global hierarchical clustering spontaneously discriminated two groups of BCLs corresponding to "luminal-like" cell lines and to "basal-like" cell lines, respectively. These groups of BCLs were also different in terms of estrogen receptor status as well as expression of epidermal growth factor receptor and other basal markers. Supervised analysis revealed various protein biomarkers with differential expression in basal-like versus luminal-like cell lines. We identified two of them as a carboxyl terminus-truncated form of ubiquitin and S100A9. In a small series of frozen human breast tumors, we confirmed that carboxyl terminus-truncated ubiquitin is observed in primary breast samples, and our results suggest its higher expression in luminal-like tumors. S100A9 up-regulation was found as part of the transcriptionally defined basal-like cluster in DNA microarrays analysis of human tumors. S100A9 association with basal subtypes as well as its poor prognosis value was demonstrated on a series of 547 tumor samples from early breast cancer deposited in a tissue microarray. Our study shows the potential of integrated genomics and proteomics profiling to improve molecular knowledge of complex tumor phenotypes and identify biomarkers with valuable diagnostic or prognostic values.
Highlights
Molecular subtypes of breast cancer with relevant biological and clinical features have been defined recently, notably ERBB2-overexpressing, basal-like, and luminallike subtypes
We examined the mRNA expression of cDNA sequences coding for ubiquitin proteins in the panel of breast cell lines (BCLs) studied
We looked at the gene signature associated with basal/luminal discrimination in a panel of human breast cancer analyzed by DNA microarrays
Summary
Molecular subtypes of breast cancer with relevant biological and clinical features have been defined recently, notably ERBB2-overexpressing, basal-like, and luminallike subtypes. If molecularly targeted approaches are available for luminal (hormonal therapy) and ERBB2 BCs (trastuzumab), no similar treatment exists for basal-like BCs, justifying the need for a better molecular definition of this subtype This definition may allow specific management and help identify novel molecular targets for innovative treatments. A promising way to complement molecular typing of tumors is to perform protein expression profiling using MS-based approaches [9] These approaches take advantage of the ability of mass spectrometers to separate peptides or proteins according to their m/z. Among MS-based approaches, SELDI-TOF technology, which couples protein separation using chromatographic surfaces (ProteinChip arrays) and direct presentation to spectrometers, was made popular as a promising way to profile complex biological samples, notably biological fluids such as serum, plasma, or urine, to identify diagnostic or prognostic biomarkers (10 –14). Our objectives were to explore how SELDI protein profiles may correlate with previously reported molecular subtypes identified in BCs and to identify specific biomarkers associated with these subtypes by taking advantage of specific MS features
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