Prognostic value ofERBBfamily mRNA expression in breast carcinomas

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Abstract
The ErbB‐driven autocrine growth pathway has been implicated in the development and progression of most common human epithelial malignancies; its blockade is therefore a promising therapeutic strategy, and several candidate drugs are currently undergoing clinical trials. Paradoxically, little is known of the expression pattern of these 4 genes in human tumors, and the clinical significance of the 2 most recently discoveredERBBgenes,ERBB3andERBB4, is unclear. We used a real‐time quantitative RT‐PCR assay to quantifyERBBfamily mRNA copy numbers in a large series of breast tumors from patients with known long‐term outcome.ERBBgene expression varied widely, by more than 2 orders of magnitude forERBB1andERBB3, more than 3 orders forERBB2and more than 4 orders forERBB4. We found a positive correlation betweenERBB3andERBB4mRNA levels, and a negative correlation between the expression of these 2 latter genes and that ofERBB1. Compared to normal breast tissue,ERBB1was underexpressed (82.3% of tumors),ERBB2(16.9%) andERBB3(46.2%) were overexpressed andERBB4was both underexpressed (24.6%) and overexpressed (29.2%). Links were also found betweenERBBstatus on the one hand and Scarff‐Bloom‐Richardson (SBR) histopathological grade and estrogen receptor alpha (ERa) status on the other hand. Relapse‐free survival (RFS) was shorter among patients withERBB3‐overexpressing tumors (p=0.0092) and longer among those withERBB4‐underexpressing tumors (p=0.0085) relative to patients with normal expression of the respective genes; in contrast, RFS was not significantly influenced byERBB1orERBB2mRNA status. OnlyERBB4status retained prognostic significance in Cox multivariate regression analysis (p=0.015). Our results point to the involvement of several ErbB‐specific ligands (amphiregulin and neuregulin 1) and enzymes or adaptor molecules (PI3K, Src, Shc and Grb7) in the ErbB pathway dysregulation associated with breast cancer. These findings reveal a complex expression pattern ofERBBgene family members in breast tumors and suggest that it is this pattern of expression, rather than the expression of individual family members, that should be taken into account when evaluating antitumoral drugs designed to target these receptors.
Funding Information
  • Comité Régional des Hauts-de-Seine de la Ligue Nationale Contre le Cancer