Understanding the Interplay between Human Epidermal Growth Factor Receptor 2 and Neuraminidase 1 on the Regulation of Fatty Acid Binding Protein 5 in Breast Cancer Cells

Abstract

Human epidermal growth factor receptor 2 (HER2), a member of the epidermal growth factor receptor (EGFR) family, accounts for 15–20% of breast cancer cases. HER2 is a glycosylated protein with sialic acid groups attached on the surface of the protein. Sialylated proteins can be regulated by enzymes called Neuraminidases 1 (Neu1) that catalyze the removal of sialic acid residues from glycoproteins. One of the oncogenes activated by the downstream signaling effector of the HER2 pathway is a protein called fatty acid binding protein 5 (FABP5). Elevated expression of FABP5 is correlated with poor prognosis in several carcinomas and overexpression of FABP5 prevents retinoic acid‐mediated growth suppression of mammary carcinoma cells. The objective of this study is to examine whether reducing Neu1 activity or its expression decreases HER2 activation and subsequently the downregulation of FABP5 in HER2 positive breast cancer cell line, MDA‐MB‐453. Using sialic acid assay, we quantitated the levels of sialic acid in MDA‐MB‐453 cells treated with oseltamivir phosphate, an inhibitor of Neu1 activity. Oseltamivir phosphate reduced the concentration of sialic acid in a dose‐dependent manner. Through western blot analysis, we demonstrated that suppressing the activity of Neu1 with ostelamivir phosphate in MDA‐MB‐453 cells reduced heregulin‐mediated induction of the active phosphorylated HER2 and its downstream target, FABP5. Furthermore, silencing Neu1 using siRNA reduced the expression of FABP5 protein expression in MDA‐MB‐453. Taken together, this data demonstrated that inhibition of Neu1 prevented heregulin‐induced HER2 activation, and in turn, regulated the expression of FABP5 in MDA‐MB‐453 cell line. We propose that these studies will contribute to the understanding of how Neu1 and HER2 communicate to modulate the expression of FABP5, Thus, Neu1 can be used as clinical target to improve the efficacy or sensitivity of retinoic acid in HER2+ breast cancer patients.Support or Funding InformationFunding was obtained through the Summer Undergraduate Research Fellowship, Office of Undergraduate Research (I.M) and the Pat Capps Covey College of Allied Health Professions Start Up Fund (P.T.) from the University of South Alabama.