Regulation of a Novel Splice Variant of Early Growth Response 4 (EGR4-S) by HER+ Signalling and HSF1 in Breast Cancer.

Simple Summary: EGR4 is known to play an important role in the proliferation of small cell lung cancer. Our research identified a new, shortened version of this protein (which we named EGR4-S), found in breast cancer but not detectable in normal breast tissue. Interestingly, our findings show that the EGR4-S expressed by breast cancer cells could be reduced by treating the cells with certain targeted cancer therapeutics. However, sustained, high-dose treatment led to EGR4-S becoming less responsive. In addition, we identified an inverse relationship between EGR4-S and molecular stress. When cancer cells were in conditions of increased molecular stress, reduced EGR4-S levels were associated with lower growth rate but enhanced properties associated with higher metastatic potential. Taken together, our research suggests further investigation of EGR4-S is warranted in order to determine its potential as a biomarker for differentiating tumours from normal tissue at the molecular level, as well as its possible resistance to targeted therapies. The zinc finger transcription factor EGR4 has previously been identified as having a critical role in the proliferation of small cell lung cancer. Here, we have identified a novel, shortened splice variant of this transcription factor (EGR4-S) that is regulated by Heat Shock Factor-1 (HSF1). Our findings demonstrate that the shortened variant (EGR4-S) is upregulated with high EGFR, HER2, and H-Ras^v12-expressing breast cell lines, and its expression is inhibited in response to HER pathway inhibitors. Protein and mRNA analyses of HER2+ human breast tumours indicated the novel EGR4-S splice variant to be preferentially expressed in tumour tissue and not detectable in patient-matched normal tissue. Knockdown of EGR4-S in the HER2-amplified breast cancer cell line SKBR3 reduced cell growth, suggesting that EGR4-S supports the growth of HER2+ tumour cells. In addition to chemical inhibitors of the HER2 pathway, EGR4-S expression was also found to be suppressed by chemical stressors and the overexpression of HSF1. Under these conditions, reduced EGR4-S levels were associated with the observed lower cell growth rate, but the augmentation of properties associated with higher metastatic potential. Taken together, these findings identify EGR4-S as a potential biomarker for HER2 pathway activation in human tumours that is regulated by HSF1. [ABSTRACT FROM AUTHOR]