Expression of EGFR isoform D is regulated by HER receptor activators in breast cancer cells

Lisandra Negrón-Vega; Elsa M Cora; Marianela Pérez-Torres; Shou-Ching Tang; Nita J Maihle; Jung Su Ryu

doi:10.1016/j.bbrep.2022.101326

Expression of EGFR isoform D is regulated by HER receptor activators in breast cancer cells

Biochem Biophys Rep. 2022 Aug 19:31:101326. doi: 10.1016/j.bbrep.2022.101326. eCollection 2022 Sep.

Authors

Lisandra Negrón-Vega¹, Elsa M Cora¹, Marianela Pérez-Torres², Shou-Ching Tang^{3

4}, Nita J Maihle^{3

4}, Jung Su Ryu⁴

Affiliations

¹ Department of Biochemistry, University of Puerto Rico-Medical Sciences Campus, PO Box 365067, San Juan, PR, 00936-5067, Puerto Rico.
² School of Pharmacy, University of Puerto Rico-Medical Sciences Campus, PO Box 365067, San Juan, PR, 00936-5067, Puerto Rico.
³ Department of Medicine, Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, MS, USA.
⁴ Department of Cell and Molecular Biology, Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, MS, USA.

Abstract

Human epidermal growth factor receptor isoform D (EGFR; isoform D) is a soluble protein from a 3 kb alternate mRNA transcript that arises from the human EGFR gene. Several studies have identified this circulating isoform of EGFR as a potential diagnostic biomarker for the detection of early stage of cancers. While the expression of the full-length EGFR (isoform A) is regulated by its cognate ligand, EGF, as well as by phorbol myristate acetate (PMA), no studies have examined the factors regulating the expression of EGFR isoform D. In this study, using breast cancer cell lines, we show that the HER receptor ligands, EGF and neuregulin (NRG-1β), as well as the phorbol ester, PMA, can increase the expression of EGFR isoform D, as well as isoform A. Our results, based on measurement of mRNA levels, suggest that EGF induced expression of both isoform A and isoform D occur through a mitogen activated protein kinase (MAPK)-dependent mechanism, and also suggest that protein kinase C is involved in PMA-induced regulation of both isoforms. We also demonstrate that NRG-1β increases isoform A and isoform D expression via the MAPK-dependent pathway, but this regulation occurs independently of phosphatidylinositol 3-kinase/Akt activation. These results suggest that regulation of EGFR isoform A and isoform D expression occur using similar mechanisms. Despite commonalities in the transcriptional regulation of these two EGFR isoforms, the half-lives of these two transcripts is quite different. Moreover, EGFR isoform D, unlike isoform A, is not post-transcriptionally modulated by EGFR activators in the breast cancer cell line MDA-MB-468.

Keywords: Breast cancer; EGF; EGFR; HER2; HER3; HER4; Neuregulin; PMA; Receptor tyrosine kinase; Regulation of gene expression; Signal transduction; sEGFR.