Prognostic value ofERBBfamily mRNA expression in breast carcinomas

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 discovered ERBB genes, ERBB3 and ERBB4, is unclear. We used a real-time quantitative RT-PCR assay to quantify ERBB family mRNA copy numbers in a large series of breast tumors from patients with known long-term outcome. ERBB gene expression varied widely, by more than 2 orders of magnitude for ERBB1 and ERBB3, more than 3 orders for ERBB2 and more than 4 orders for ERBB4. We found a positive correlation between ERBB3 and ERBB4 mRNA levels, and a negative correlation between the expression of these 2 latter genes and that of ERBB1. Compared to normal breast tissue, ERBB1 was underexpressed (82.3% of tumors), ERBB2 (16.9%) and ERBB3 (46.2%) were overexpressed and ERBB4 was both underexpressed (24.6%) and overexpressed (29.2%). Links were also found between ERBB status 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 with ERBB3-overexpressing tumors (p‫)2900.0؍‬ and longer among those with ERBB4-underexpressing tumors (p‫)5800.0؍‬ relative to patients with normal expression of the respective genes; in contrast, RFS was not significantly influenced by ERBB1 or ERBB2 mRNA status. Only ERBB4 status retained prognostic significance in Cox multivariate regression analysis (p‫.)510.0؍‬ 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 of ERBB gene 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. © 2003 Wiley-Liss, Inc. Key words: breast cancer; ERBB family gene expression; real-time RT-PCR quantification; prognostic valueIn multicellular organisms, communication among cells is an absolute requirement for the regulation of complex biological processes such as growth, differentiation, motility and death. Receptor tyrosine kinases, which are the primary mediators of many intercellular signals, exist in structurally distinct forms that can be grouped into about 20 functionally related subfamilies. 1 ErbB proteins belong to subclass I of the superfamily of receptor tyrosine kinases. The ErbB family has evolved from a single ligandreceptor combination in Caenorhabditis elegans, 2 to 1 receptor and 4 ligands in Drosophila melanogaster, 3 and to 4 ErbB receptors that bin...

Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin

“…Most metastatic breast cancers show expression for either EGFR or erbB2, and less often for both (Grupka et al, 2004). In contrast, coexpression of erbB3 and erbB2 is frequently observed in breast cancers (Bieche et al, 2003) and cell lines (deFazio et al, 2000). It has been reported that erbB2 requires erbB3 to promote breast cancer cell proliferation (Holbro et al, 2003); and erbB3 has a critical role in erbB2 altered breast cancers (Lee-Hoeflich et al, 2008).…”

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

“…Grb7 is an especially promising cancer target as the encoding gene maps closely to the ErbB2 gene on human chromosome 17q12 and is found co-amplified and overexpressed in a subset of breast, esophageal and gastric cancers (Stein et al, 1994;Kishi et al, 1997;Tanaka et al, 1997;Fiddes et al, 1998;Kauraniemi et al, 2001;Varis et al, 2002;Andrechek et al, 2003;Bieche et al, 2003). Analysis of chromosome 17q12 in a variety of different breast cancer cell lines Grb7 was found to have a high DNA copy number with a high level of ErbB2 co-expression (Kauraniemi et al, 2001).…”

“…Similar findings were observed in ErbB2-induced mammary tumours from transgenic mice (Andrechek et al, 2003). In addition, Grb7 expression had the strongest association with ErbB2 expression in 54 primary breast tumours analysed by real-time quantitative RT-PCR (Bieche et al, 2003). Co-expression of Grb7 with ErbB2 was detected in 31% of esophageal carcinomas and was significantly correlated with extramucosal tumour invasion (Tanaka et al, 1997).…”

Estrogen receptor-positive mammary tumorigenesis in TGFα transgenic mice progresses with progesterone receptor loss

“…ER is present in epithelial and nonepithelial mammary cells, increasing in hyperplasias (Lee et al, 2006). In addition, reduction in ER and, more radically, PR transcripts in NRLTGFa mice parallels clinical findings in which breast cancers expressing TGFa and ErbB1 had reduced ER (Bieche et al, 2003).…”