Dual activation of pathways regulated by steroid receptors and peptide growth factors in primary prostate cancer revealed by Factor Analysis of microarray data.
BACKGROUND
We use an approach based on Factor Analysis to analyze datasets generated for transcriptional profiling. The method groups samples into biologically relevant categories, and enables the identification of genes and pathways most significantly associated to each phenotypic group, while allowing for the participation of a given gene in more than one cluster. Genes assigned to each cluster are used for the detection of pathways predominantly activated in that cluster by finding statistically significant associated GO terms. We tested the approach with a published dataset of microarray experiments in yeast. Upon validation with the yeast dataset, we applied the technique to a prostate cancer dataset.


RESULTS
Two major pathways are shown to be activated in organ-confined, non-metastatic prostate cancer: those regulated by the androgen receptor and by receptor tyrosine kinases. A number of gene markers (HER3, IQGAP2 and POR1) highlighted by the software and related to the later pathway have been validated experimentally a posteriori on independent samples.


CONCLUSIONS
Using a new microarray analysis tool followed by a posteriori experimental validation of the results, we have confirmed several putative markers of malignancy associated with peptide growth factor signalling in prostate cancer and revealed others, most notably ERRB3 (HER3). Our study suggest that, in primary prostate cancer, HER3, together or not with HER4, rather than in receptor complexes involving HER2, could play an important role in the biology of these tumors. These results provide new evidence for the role of receptor tyrosine kinases in the establishment and progression of prostate cancer.
Lozano
Juan Jose
JJ
Bioinformatics Unit, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. juanjo.lozano@crg.es
Soler
Marta
M
Bermudo
Raquel
R
Abia
David
D
Fernandez
Pedro L
PL
Thomson
Timothy M
TM
Ortiz
Angel R
AR
D014408:Biomarkers, Tumor; D016000:Cluster Analysis; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005800:Genes, Fungal; D016681:Genome, Fungal; D005838:Genotype; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007834:Lasers; D008297:Male; D008957:Models, Genetic; D015233:Models, Statistical; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010455:Peptides / Q000737:chemistry*; D010641:Phenotype; D010802:Phylogeny; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D066247:Receptor, ErbB-4; D011944:Receptors, Androgen / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D006133:Growth Substances; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D011944:Receptors, Androgen; D011987:Receptors, Steroid; C587689:ERBB4 protein, human