Gene expression patterns and profile changes pre- and post-erlotinib treatment in patients with metastatic breast cancer.
OBJECTIVE
To delineate gene expression patterns and profile changes in metastatic tumor biopsies at baseline and 1 month after treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib in patients with metastatic breast cancer.


METHODS
Patients were treated with 150 mg of oral erlotinib daily. Gene expression profiles were measured with Affymetrix U133A GeneChip and immunohistochemistry was used to validate microarray findings.


RESULTS
Estrogen receptor (ER) status by immunohistochemistry is nearly coincided with the two major expression clusters determined by expression of genes using unsupervised hierarchical clustering analysis. One of 10 patients had an EGFR-positive tumor detected by both microarray and immunohistochemistry. In this tumor, tissue inhibitor of metalloproteinases-3 and collagen type 1 alpha 2, which are the EGF-down-regulated growth repressors, were significantly increased by erlotinib. Gene changes in EGFR-negative tumors are those of G-protein-linked and cell surface receptor-linked signaling. Gene ontology comparison analysis pretreatment and posttreatment in EGFR-negative tumors revealed biological process categories that have more genes differentially expressed than expected by chance. Among 495 gene ontology categories, the significant differed gene ontology groups include G-protein-coupled receptor protein signaling (34 genes, P = 0.002) and cell surface receptor-linked signal transduction (74 genes, P = 0.007).


CONCLUSIONS
ER status reflects the major difference in gene expression pattern in metastatic breast cancer. Erlotinib had effects on genes of EGFR signaling pathway in the EGFR-positive tumor and on gene ontology biological process categories or genes that have function in signal transduction in EGFR-negative tumors.
Yang
Sherry X
SX
Cancer Therapeutics Branch in Center for Cancer Research , National Cancer Institute, NIH, Bethesda, Maryland 20889, USA. xy32m@nih.gov
Simon
Richard M
RM
Tan
Antoinette R
AR
Nguyen
Diana
D
Swain
Sandra M
SM
D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D009363:Neoplasm Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000378:metabolism
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011960:Receptors, Estrogen; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors