Targeting glypicans through EGFR and JAK/STAT signaling axes drives breast cancer progression

Abstract

Extracellular matrix (ECM) and its dynamic remodeling contribute to the progression of breast cancer, the most prevailing cancer type in women. Glypicans (GPCs) function as cell co‐receptors by facilitating the formation of ligand–receptor complexes. An important regulator in the context of breast cancer progression is the JAK/STAT signaling pathway that oversees the expression of genes associated with cancer cell characteristics. Epidermal growth factor receptor (EGFR) is a pivotal player in this process. The aim of this study is to examine the effect of the EGFR and JAK/STAT signaling pathways on GPCs expression in breast cancer cells with different estrogen receptor (ER) status, depicting different breast cancer subtypes. To this end, the ERα‐positive MCF‐7, and the ERβ‐positive MDA‐MB‐231 breast cancer cell lines were evaluated in terms of the impact of downstream inhibition of both pathways on the functional properties as well as the expression of GPCs 1‐6 genes. Notably, the downstream inhibition of both EGFR and JAK/STAT cascades mitigate cell proliferation and migration, while increasing cell adhesion on collagen type I in an ER‐independent manner. However, the inhibition exhibited a cell‐line‐dependent effect on GPC expression, as in MCF‐7 cells GPCs expression is mostly downregulated excepting GPC‐4 and GPC‐5. Conversely, in MDA‐MB‐231 cells, EGFR and JAK/STAT activation is essential for maintaining GPCs at low levels. Additionally, STRING analysis identified the small leucine‐rich PG decorin as a putative link between all GPCs and EGFR. Subsequently, a deeper understanding on the effect of EGFR and JAK/STAT signaling may shed light into the role and interplay between GPCs and decorin in breast cancer progression, thus contributing to novel therapeutic solutions.