Expression and differential signaling of heregulins in pancreatic cancer cells

Abstract

The EGF family of ligands and receptors plays an important role in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) and contributes to its aggressiveness. A number of molecular approaches have been developed to block these pathways, and studies have already proven the clinical benefit of this concept in PDAC. In the present study, we sought to determine the potential role of heregulins (HRGs), a family of EGF-like growth factors, in PDAC. Quantitative RT-PCR analysis revealed that HRGs as well as its signaling ErbB receptors were present in 4 of 4 human pancreatic cancer cell lines (PCCL). HRG-b1 stimulated the growth of 3 of 4 PCCL, whereas HRG-a1 inhibited cell growth in 3 of 4 cell lines. Responses towards HRGs could in part be predicted by ErbB2 and ErbB3 expression levels. HRGs induced phosphorylation of different ErbB receptors as well as activation of MAPK, p38MAPK, JNK and PI3K in a cell-and ligand-specific manner. In vivo, HRG was upregulated in pancreatic cancer tissues and localized predominantly in the cancer cells. High HRG-b levels but not HRG-a levels were associated with decreased patient survival. In conclusion, HRG is expressed by pancreatic cancer cells and influences pancreatic cancer cell growth and patient survival. ' 2006 Wiley-Liss, Inc.

Role of heregulin in human cancer

“…In vivo, HRG is up-regulated in pancreatic cancer tissues and localized predominantly in the cancer cells. High HRG-b levels but not HRG-a levels are associated with decreased patient survival [187]. Interestingly, HRGs can also induce pancreatic cancer cell growth without the presence or activation of ErbB3 and ErbB4, pointing to a receptor-independent role in pancreatic tumor development.…”

Confirmation of DNA Microarray-Derived Differentially Expressed Genes in Pancreatic Cancer Using Quantitative RT-PCR

“…Among others, the epidermal growth factor receptor itself (EGFR [5,6] ) as well as HER2/ErbB2 [7] and HER3/ErbB3 [8] , along with other EGFR family members, has been proven to be frequently up-regulated in pancreatic tumors, which correlates with reduced survival and a worsened prognosis in PDAC patients. In addition to increased expression of the receptors themselves, up-regulation of the corresponding ligands, such as EGF [5,6] , TGF-␣ [5,6] , HB-EGF [9] , epiregulin [10] , betacellulin [11] , amphiregulin [12] , and heregulins [13] , has also been observed in PDAC samples. Through autocrine or paracrine action, these factors stimulate tumor cell growth and contribute to enhanced aggressiveness and disease progression.…”

Prognostic significance of serum ERBB3 and ERBB4 mRNA in lung adenocarcinoma patients

“…Patients treated with chemotherapeutic agents had more than two times reduced overall survival than treated with gefitinib. Several studies reported high ERBB3 expression in pancreatic cancer mainly observed in advanced stage and associated with poor overall survival [31,32]. J S Liles et al [33] analysed operative pancreatic adenocarcinoma specimens and found that ERBB3 was expressed in all tumour specimens, Koutsopoulos et al also observed that strong overexpression of ERBB3 was significantly associated with poor overall survival in non-small cell lung cancer (NSCLC) [34], and Kawano et al [35] also revealed that ERBB3 mRNA expression levels were significantly higher in lung adenocarcinoma patients.…”