Poster Presentation 35th Lorne Cancer Conference 2023

Regulation of a novel splice variant of Early Growth Response 4 (EGR4-S) by HER+ signalling and HSF1 in breast cancer (#135)

Jeremy M Drake 1 2 , Benjamin J Lang 3 , Martin E Guerrero-Gimenez 4 , Jack Bolton 2 , Christopher A Dow 5 6 , Stuart K Calderwood 3 , John T Price 2 7 8 9 , Chau H Nguyen 2 10
  1. ProMetTre Cancer Research, South Melbourne, VIC, Australia
  2. College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia
  3. Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  4. Laboratory of Oncology, Institute of Medicine and Experimental Biology of Cuyo (IMBECU), Mendoza, Argentina
  5. Dorevitch Pathology, Western Hospital, Melbourne, Victoria, Australia
  6. Department of Medicine, University of Melbourne, Melbourne , Victoria, Australia
  7. Institute for Health and Sport, Victoria University, Melbourne, Victoria, Australia
  8. Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, Melbourne, Victoria, Australia
  9. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia
  10. Science and Technology Division, The International Commission on Missing Persons, The Hague, The Netherlands

The transcription factor "Early Growth Response 4" (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 EGR4-S variant is upregulated in breast cell lines expressing high EGFR, HER2, and H-Rasv12, and that EGR4-S expression is inhibited in response to targeted cancer therapeutics acting on the HER pathway. However, sustained, high-dose therapy led to EGR4-S becoming less responsive. 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 targeted inhibitors of the HER2 pathway, EGR4-S expression was also found to be suppressed when molecular stress was elevated (with both chemical stressors or the overexpression of HSF1). Under conditions of increased molecular stress, 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, 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.