Abstract 3337: LRIG1 decreases cell proliferation and motility through downregulation of ErbB2 611-CTF

Abstract

The receptor ErbB2 is a membrane bound protein that controls important cell functions including cell cycle progression; deregulated expression of this protein is associated with the development of a variety of cancer types. Notably, ErbB2 over-expression is observed in approximately 25% of human breast tumors. Trastuzumab, an FDA approved therapeutic currently used to treat ErbB2 positive breast cancer patients, is a monoclonal antibody that directly binds the ErbB2 extracellular domain. Unfortunately, only a fraction of patients treated with trastuzumab durably respond to the treatment. Moreover, patients that are treated long term with this antibody develop resistance. One of the proposed mechanisms of trastuzumab resistance is the expression of 611-CTF, a C-terminal fragment of ErbB2 which lacks most of its extracellular domain. Remarkably, 611-CTF is hyperactive and has been associated with increased cell migration, tumor progression and metastasis. Currently nothing is known regarding mechanisms which lead to 611-CTF down-regulation. This represents a significant knowledge gap in our understanding of 611-CTF and receptor fragments in general. Since 611-CTF is associated with poor clinical outcome and therapeutic resistance, it is essential to clarify the mechanisms by which this ErbB2 fragment is regulated. This knowledge could ultimately lead to the development of new therapeutics which could improve the response rate of 611-CTF-positive breast cancer. LRIG1 is a tumor suppressor that directly interacts with ErbB2 leading to receptor degradation. In this study we examined whether 611-CTF is susceptible to LRIG1-mediated down-regulation. We find that these proteins interact and that expression of LRIG1 is sufficient to decrease 611-CTF protein expression in three different cell lines. Furthermore, LRIG1 is capable of reducing 611-CTF-driven tumor cell proliferation and migration. Our results are unexpected because LRIG1 is thought to recognize its targets through mutual extracellular domain interactions and 611-CTF lacks a large portion of the ErbB2 extracellular domain. Citation Format: Maria E. Cedano-Prieto. LRIG1 decreases cell proliferation and motility through downregulation of ErbB2 611-CTF. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3337. doi:10.1158/1538-7445.AM2014-3337