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

Jeremy M Drake; Benjamin J Lang; Martin Eduardo Guerrero-Gimenez; Jack Bolton; Christopher A Dow; Stuart K Calderwood; John T Price; Chau H Nguyen

doi:10.3390/cancers14061567

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

Cancers (Basel). 2022 Mar 18;14(6):1567. doi: 10.3390/cancers14061567.

Authors

Jeremy M Drake^{1

2}, Benjamin J Lang³, Martin Eduardo Guerrero-Gimenez⁴, Jack Bolton², Christopher A Dow^{5

6}, Stuart K Calderwood³, John T Price^{2

7

8

9}, Chau H Nguyen^{2

9}

Affiliations

¹ ProMetTre Cancer Research, Melbourne 3205, Australia.
² College of Health and Biomedicine, Victoria University, Melbourne 8001, Australia.
³ Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁴ Laboratory of Oncology, Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Scientific and Technical Research Council (CONICET), Mendoza 5500, Argentina.
⁵ Dorevitch Pathology, Western Hospital, Melbourne 3011, Australia.
⁶ Department of Medicine, University of Melbourne, Melbourne 3052, Australia.
⁷ Institute for Health and Sport, Victoria University, Melbourne 8001, Australia.
⁸ Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, Melbourne 8001, Australia.
⁹ Department of Biochemistry and Molecular Biology, Monash University, Clayton 3800, Australia.

Abstract

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.

Keywords: EGR4; HER2; HSF1; breast cancer; molecular stress.