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

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.

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

“…It has been reported that in patients with lung, ovarian and oesophageal cancers, high expression of PARK7 predicts a poor outcome [96]. Moreover, high expression of PARK7 in breast cancer potentiates HER3 signaling and therefore may serve as a target for molecular therapies [97]. In our tissue samples we have identified 4 isoforms one of which, ubiquitous, with an expression level of 2.4x, while the others were sporadics.…”

Cytoprotective mechanisms of DJ-1 against oxidative stress through modulating ERK1/2 and ASK1 signal transduction

“…(2) DJ-1, but not its L166P mutant, protects cells from oxidative injury by activating ERK1/2 and MEK1/2 [12] . The over-expression of wild-type DJ-1 up-regulates ERK1/2 and MEK1/2 phosphorylation [12] , while knock-down of DJ-1 down-regulates phosphorylated ERK1/2 [42] . (3) Under oxidative conditions, DJ-1, but not its C106S mutant, sequesters the transcription factor p53 away from promoters, resulting in down-regulation of the ERK1/2 inhibitor, DUSP1 [40] .…”

“…For example, over-expression of wild-type (WT) DJ-1 in COS-7 or MN9D cells up-regulates ERK1/2 and MEK1/2 phosphorylation, while L166P mutant DJ-1, which is linked to Parkinson's disease, cannot enhance ERK1/2 or MEK1/2 phosphorylation [12] . In cancer cell models (T47-D and MCF-7), knock-down of DJ-1 using shRNA leads to down-regulation of phosphorylated ERK1/2 and decreased cell proliferation [42] .…”

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

“…It has been reported that in patients with lung, ovarian and oesophageal cancers, high expression of PARK7 predicts a poor outcome [ 100 ]. Moreover, high expression of PARK7 in breast cancer potentiates HER3 signaling and therefore may serve as a target for molecular therapies [ 101 ]. In our tissue samples, we have identified four isoforms one of which was ubiquitous and moderately over-expressed on the non-tumoral tissues.…”