Novel association of DJ-1 with HER3 potentiates HER3 activation and signaling in cancer.

// Shu Zhang 1, 2, * , Seema Mukherjee 1, * , Xuejun Fan 1 , Ahmad Salameh 1 , Kalpana Mujoo 1, 3 , Zhao Huang 1, 4 , Leike Li 1 , Georgina To’a Salazar 1 , Ningyan Zhang 1 , Zhiqiang An 1 1 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA 2 Current address: Clinical Research Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 3 Current address: Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas, USA 4 Current address: Stemcentrx, Inc., South San Francisco, California, USA * These authors have contributed equally to this work Correspondence to: Ningyan Zhang, email: Ningyan.zhang@uth.tmc.edu Zhiqiang An, email: zhiqiang.an@uth.tmc.edu Keywords: HER3, DJ-1, anti-HER3 monoclonal antibody, biomarker, cancer Received: June 07, 2016     Accepted: August 15, 2016     Published: August 25, 2016 ABSTRACT HER3/ErbB3 has emerged as a new therapeutic target for cancer. Currently, more than a dozen anti-HER3 antibodies are in clinical trials for treatment of various cancers. However, limited understanding of the complex HER3 signaling in cancer and lack of established biomarkers have made it challenging to stratify cancer patients who can benefit from HER3 targeted therapies. In this study, we identified DJ-1/PARK7 (Parkinson Protein 7) as a novel interaction partner of HER3 and demonstrated the potential of DJ-1 as a biomarker for anti-HER3 cancer therapy. DJ-1 association with HER3 protects HER3 from ubiquitination and degradation through the proteasomal pathway in breast cancer cells. However, neuregulin 1 (NRG-1) mediated HER3 activation results in a reduced association of DJ-1 with HER3. DJ-1 shRNA knockdown in cancer cells resulted in decreased levels of HER3 and its downstream signaling through the PI3K/AKT and Ras/Raf/ERK pathways. DJ-1 shRNA knockdown cancer cells significantly reduced cell proliferation and migration in vitro and tumor growth in vivo . Conversely, overexpression of DJ-1 increased HER3 levels and promoted cancer cell proliferation in vitro and tumor growth in vivo . Notably, cancer cells with high DJ-1 expression showed more sensitivity than DJ-1 knockdown cells to anti-HER3 antibody inhibition. In addition, there was a significant co-expression of HER3 and DJ-1 in tumor tissues of breast cancer patients. Taken together, these results suggest that high DJ-1 expression in breast cancer cells predicts elevated HER3 signaling and may therefore serve as a biomarker for HER3 targeted antibody cancer therapies.