Abstract 3033: Negative regulation of ErbB2 611-CTF by LRIG1.

Abstract

Abstract The ErbB family of receptor tyrosine kinases is composed of four members: EGFR, ErbB2, ErbB3, and ErbB4; these are membrane bound proteins that control important cell functions through the activation of signaling cascades such as the Ras-mitogen-activated protein kinase (MAPK) and the phosphatidylinoditol3-kinase (PI3K)-Akt pathways. Deregulated expression of the ErbB family by gene amplification and/or protein over-expression is associated with the development and progression of a variety of cancer types. Notably, ErbB2 over expression is observed in approximately 25% of human breast tumors. The negative regulator, LRIG1 is a transmembrane protein that can directly interact with all members of the ErbB family leading to receptor degradation. In addition, in vitro experiments have shown that loss of LRIG1 is sufficient to drive an increase in ErbB2 protein levels and signaling while ectopic expression of LRIG1 decreases ErbB protein expression and signaling. Recently, a group of ErbB2 C-terminal fragments (CTFs) collectively known as “p95HER2”have captured the attention of the scientific community because a) they are capable of inducing more aggressive tumors compared with those expressing full length ErbB2 and because b) they have been directly implicated in therapeutic resistance to Herceptin, the standard of care for ErbB2-positive breast cancer. ErbB2 CTFsare generated by two independent mechanisms; 1) initiation of translation at alternative methionine codons, producing two fragments known as 611-CTF and 687-CTF; 2) Proteolytic shedding of full length ErbB2, generating 648-CTF and 676-CTF fragments. Clinical data indicate that p95HER2 positive patients have lower survival rates compared with those expressing low p95HER2 levels.Among the p95HER fragments, 611-CTF is the most interesting because it is hyperactive and has been associated with increased cell migration, tumor progression and metastasis. Currently, nothing is known of the mechanisms which govern p95HER2 down-regulation. Insight into these mechanisms could ultimately lead to the development of new therapeutics which may improve the response rate of p95HER2-positive breast cancer. In this study we examined whether 611-CTF is susceptible to LRIG1-mediated down-regulation. We find that these proteins interact and that ectopic expression of LRIG1 is sufficient to decrease 611-CTF protein expression in three different cell lines. Furthermore, LRIG1 is capable of reducing 611-driven tumor cell proliferation and migration. Our results are surprising because LRIG1 is thought to recognize its targets through mutual ecto-domain interactions and 611-CTF lacks a large portion of the ErbB2 ecto-domain. Citation Format: Maria E. Cedano-Prieto, Lakmal Kotelawala, Colleen Sweeney. Negative regulation of ErbB2 611-CTF by LRIG1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3033. doi:10.1158/1538-7445.AM2013-3033 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.