Evaluation of the coordinated actions of estrogen receptors with epidermal growth factor receptor and insulin‐like growth factor receptor in the expression of cell surface heparan sulfate proteoglycans and cell motility in breast cancer cells

Abstract

Estradiol (E2)-estrogen receptor (ER) actions are implicated in initiation, growth and progression of hormone-dependent breast cancer. Crosstalk between ERs, epidermal growth factor receptor (EGFR) and/or insulin-like growth factor receptor (IGFR) is critical for the observed resistance to endocrine therapies. Cell surface heparan sulfate proteoglycans (HSPGs) are principal mediators of cancer cell properties and the E2-ER pathway as well as those activated by EGFR and IGFR have significant roles in regulating the expression of certain cell surface HSPGs, such as syndecan-2 (SDC-2), syndecan-4 (SDC-4) and glypican-1. In this study, we therefore evaluated the role of EGFR-IGFR signaling on the constitutive expression and E2-mediated expression of ERs and HSPGs as well as the effect of E2-ERs and IGFR/EGFR-mediated cell migration in ERa+ (MCF-7) and ERb+ (MDA-MB-231) breast cancer cells using specific intracellular inhibitors of EGFR and IGFR. We report that the expression of ERa is mainly enhanced by IGFR, whereas ERb expression is mainly coordinated by EGFR. Moreover, constitutive SDC-2 expression in ERa+ and ERb+ cells is mainly mediated through the IGFR, whereas in ERa+ E2-treated cells EGFR is the active one. In contrast, SDC-4 expression is regulated by IGFR in the presence and absence of E2. E2 also seems to diminish the inhibitory effect of EGFR and IGFR inhibitors in breast cancer cell migration. These data suggest that the coordinated action of ERs with EGFR and/or IGFR is of crucial importance, providing potential targets for designing and developing novel multi-potent agents for endocrine therapies.

Carbohydrate-Containing Molecules as Potential Biomarkers in Colon Cancer

“…There is still controversy over the expression of syndecans in cancer. The Karamanos group showed that syndecans-2 and -4 as well as glypican-1 were overexpressed in the breast cancer lines compared to normal mammary cells (Tsonis et al, 2013). In contrast, Vicente et al reported that syndecan-2 was highly expressed and the mRNA expression level of syndecan-1 and -4 were…”

Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells

“…In earlier studies, we had noted that E2/ERα signaling pathway makes a key partner of the receptors for EGF and IGF as to regulate the expression of ECM components in breast cancer cells [19][20][21][22]. In the present study, we provide data to show that induced loss of ERα results in potent EMT, striking changes in the expression profile of specific matrix macromolecules and in breast cancer cell's functional properties associated with an aggressive potential, highlighting the potential nodal role of ERα and matrix effectors in endocrine breast cancer resistance.…”

Epithelial to Mesenchymal Transition Promotes Breast Cancer Progression via a Fibronectin-dependent STAT3 Signaling Pathway

“…Other potentially critical factors that may be relevant in TNBC include the interplay between EGFR and insulin-like growth factor receptor signaling systems and production of cell surface effectors such as the subclass of heparin sulfate proteoglycans known as syndecans (52)(53)(54)(55)(56). Understanding how these different factors are integrated to drive metastatic progression will provide the Somewhat surprisingly, our data also appear to exclude a role for autocrine IL-6 because EMT programs fail to diminish the ability of NME cells to activate STAT3 in response to exogenous IL-6.…”