Abstract
Earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) requires better understanding of the mechanisms driving tumorigenesis. In this context, depletion of Epidermal Growth Factor Receptor (EGFR) is known to impair development of PDAC-initiating lesions called acinar-to-ductal metaplasia (ADM) and Pancreatic Intraepithelial Neoplasia (PanIN). In contrast, the role of v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), the preferred dimerization partner of EGFR, remains poorly understood. Here, using a mouse model with inactivation of Erbb2 in pancreatic acinar cells, we found that Erbb2 is dispensable for inflammation- and KRasG12D-induced development of ADM and PanIN. A mathematical model of EGFR/ERBB2-KRAS signaling, which was calibrated on mouse and human data, supported the observed roles of EGFR and ERBB2. However, this model also predicted that overexpression of ERBB2 stimulates ERBB/KRAS signaling; this prediction was validated experimentally. We conclude that EGFR and ERBB2 differentially impact ERBB signaling during PDAC tumorigenesis, and that the oncogenic potential of ERBB2 is only manifested when it is overexpressed. Therefore, the level of ERBB2, not only its mere presence, needs to be considered when designing therapies targeting ERBB signaling.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a 5-year survival rate of about 7%
Since ERBB2 is the preferred dimerization partner of EGFR10,11, we hypothesized that ERBB2 is important for pancreatic tumorigenesis
In WT and ElaCER KrasG12D pancreas, in the absence of inflammation, ERBB2 was detected at the basolateral domains of the duct cells; ERBB2 labeling in acini was not membrane-associated and was considered non-specific
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a 5-year survival rate of about 7%. Unlike breast cancer where ERBB2 is frequently amplified and plays an important role in tumor progression, ERBB2 amplification is detected at low frequency in PDAC14. This contrasts with the high number of PDAC cases (about 50%) that show a detectable level of ERBB2 expression, and with the high expression of ERBB2 correlating with a higher grade of cellular atypia[15]. In a mouse model of PDAC, phosphorylation of ERK, a kinase downstream of EGFR and ERBB2, correlates better with the expression of ERBB2 than with that of EGFR6 These observations suggest that ERBB2 plays a role in PDAC tumorigenesis. We find that the function of ERBB2 in pancreatic tumorigenesis differs from that of EGFR and is strongly dependent on its level of expression
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