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.
Highlights
The EGFR/HER/ErbB family of receptor tyrosine kinases is involved in complex and tightly controlled signaling pathways for the regulation of multiple cellular processes such as cell proliferation and organogenesis
We report for the first time that DJ-1 interacts with the C-terminal tail of HER3 and modulates HER3 mediated signaling and function in cancer cells
We showed in this study that DJ-1 modulates HER3 protein stability by delaying the ubiquitination mediated proteasomal degradation of HER3
Summary
The EGFR/HER/ErbB family of receptor tyrosine kinases is involved in complex and tightly controlled signaling pathways for the regulation of multiple cellular processes such as cell proliferation and organogenesis. Of the four members in the family, EGFR and HER2 are well-established proto-oncogenes, and a number of cancer therapeutics targeting EGFR and HER2 are currently in clinical use [2]. Due to the lack of intrinsic kinase activity, the importance of HER3 signaling in cancer was not recognized until it was shown to have an important role in acquired resistance to EGFR targeting cancer therapies [3, 4]. HER3 is emerging as a promising cancer target and multiple anti-HER3 antibodies are currently in clinical trials [10]. The lack of biomarkers for HER3-driven cancer poses a big challenge for the clinical development of HER3 targeting antibody therapies [10]
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