Abstract 4408: Her2 C terminal PDZ binding domain interacting with DLG1 is required for radioresistance through induction of EMT and loss of epithelial polarity

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 19_Supplement; p. 4408
• Main Authors: Lin, Dong, Zhang, Xiaodi, Eldridge, Angela, Fan, Ming, Menaa, Cheikh, Li, Jianjian
• Format: Journal Article
• Language: English
• Published: 01.10.2014
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-4408

Abstract The tyrosine kinase receptor HER2 (ErbB2/neu) is predominantly localized to the basolateral membrane of the epithelium and has been implicated in mammary tumorigenesis as well as in resistance to chemotherapy and radiation. Here we demonstrate that HER2 interacts with discs large 1 (DLG1) that is one of PDZ domain proteins expressed at the basolateral membrane of human breast epithelial cells and plays an important role in the establishment and maintenance of epithelial polarity in Drosophila. However, either loss of the last 6 C-terminal amino acids (HER2-Δ1250-1255) or a valine-to-alanine C-terminal substitution (HER2-V1255A) in HER2, abrogates the interaction with DLG1. In contrast, either PDZ domain 1 or 3 within Dlg1 is required for interaction with HER2. Moreover, HER2-Δ1250-1255- or HER2-V1255A-expressing MCF10A human breast epithelial cells show the reduction of mesenchymal-to-epithelial transition (EMT) proteins including vimentin and Snail. In addition, HER2-wt cells promotes EMT as shown by down-regulation of E-cadherin and upregulation of vimentin and Snail. Taken together, these results indicate that C-terminal PDZ binding domain in HER2 modulates biological functions of HER2. These results reveal new insight into the structure and function of HER2, which may guide the design and development of new anti-cancer targets to treat HER2-positive breast cancer. Citation Format: Dong Lin, Xiaodi Zhang, Angela Eldridge, Ming Fan, Cheikh Menaa, Jianjian Li. Her2 C terminal PDZ binding domain interacting with DLG1 is required for radioresistance through induction of EMT and loss of epithelial polarity. [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 4408. doi:10.1158/1538-7445.AM2014-4408