EGFR is a pivotal player of the E2/ERβ – mediated functional properties, aggressiveness, and stemness in triple‐negative breast cancer cells

Abstract

Triple‐negative breast cancer (TNBC) is defined by aggressive behavior, limited response to chemotherapy and lower overall survival rates. The increased metastatic potential of TNBC is a combined result of extensive extracellular matrix (ECM) remodeling that leads to cytoskeleton rearrangement and activation of epithelial‐to‐mesenchymal transition (EMT). The overexpression of epidermal growth factor receptor (EGFR) in TNBC tumors has been linked to induced expression of EMT‐related molecules. EMT activation has often been associated with increased metastasis and stemness. Recently, we described the crucial role of EGFR/estrogen receptor beta (ERβ) interplay in the regulation of invasion and cell–matrix interactions. In this study, we report on the EGFR‐ERβ functional relationship in connection to the aggressiveness and cancer stem cell (CSC)‐like characteristics of TNBC cells. ERβ‐suppressed and MDA‐MB‐231 cells were subjected to downstream EGFR inhibition and/or estradiol stimulation to assess alterations in functional parameters as well as in morphological characteristics, studied by scanning electron, atomic force, and immunofluorescence microscopies. Moreover, the expression and localization of key EMT and CSC‐related markers were also evaluated by real‐time qPCR, immunofluorescence microscopy, and flow cytometry. EGFR inhibition resulted in an overall suppression of aggressive functional characteristics, which occurred in an ERβ‐mediated manner. These changes could be attributed to a reduction, at the molecular level, of EMT and stemness‐linked markers, most notably reduced expression of Notch signaling constituents and the cell surface proteoglycan, syndecan‐1. Collectively, our study highlights the importance of EGFR signaling as a key effector of aggressiveness, EMT, and stemness in an ERβ‐dependent way in TNBC.

Matrix Metalloproteinase-2-Responsive Surface-Changeable Liposomes Decorated by Multifunctional Peptides to Overcome the Drug Resistance of Triple-Negative Breast Cancer through Enhanced Targeting and Penetrability

“…30,31 Additionally, the overexpression of EGFR was also proven in drug-resistant TNBC cells and involved in the high aggressiveness and lethality in patients. 32 Our previous studies also confirmed that EGFR was an effective target for the targeted therapy of TNBC, and several peptide ligands toward EGFR were identified through highthroughput screening of the OBOC library. 33,34 Thus, we hypothesized that screening EGFR-targeting ligands to achieve tumor-targeted therapy might be a promising strategy for the treatment of drug-resistant TNBC.…”

“…Overexpression of EGFR is frequently associated with tumor metastasis and recurrence . In a previous study, researchers identified an EGFR-targeted peptide with high specificity and affinity through phage display technology, which exhibits great potential in tumor-targeted therapy and diagnosis. , Additionally, the overexpression of EGFR was also proven in drug-resistant TNBC cells and involved in the high aggressiveness and lethality in patients . Our previous studies also confirmed that EGFR was an effective target for the targeted therapy of TNBC, and several peptide ligands toward EGFR were identified through high-throughput screening of the OBOC library. , Thus, we hypothesized that screening EGFR-targeting ligands to achieve tumor-targeted therapy might be a promising strategy for the treatment of drug-resistant TNBC.…”

ESR2 Drives Mesenchymal-to-Epithelial Transition in Triple-Negative Breast Cancer and Tumorigenesis In Vivo

“…In this study, we reported that high ESR2 expression rates have been correlated to decreased overall survival rates in breast cancer patients diagnosed with invasive breast carcinoma. Recent reports indicate that ERb target genes mostly regulate cell survival, movement, and growth (50), and that ERb signaling pathway intersects with EGFR cascade to mediate TNBC cell morphology and stemness (13,15). These data have been corroborated by the strong implication of ERb in EMT process since it acts as EMT promoter by activating the TGFb/Smad3 pathway to promote tumor growth and invasion in metastatic renal cell carcinoma (51).…”

“…The discovery of ERb in 1996 as the second nuclear receptor for steroid/thyroid hormones (i.e., 17b-estradiol, E2), after ERa, reserved a new era in the diagnosis, survival estimation and therapeutic targeting of breast cancer (12). While less well established, ERb dynamically communicates with major matrix components, including PGs and epidermal growth factor receptor (EGFR) to stimulate cancer cell behavior, epithelialto-mesenchymal transition (EMT) and stem-like characteristics (13)(14)(15).…”

Trends in extracellular matrix biology

“…For example, higher MMPs expression and activity levels guides invasion and metastasis via, among others, promotion of invadopodia formation [ 48 , 50 ]. In addition, SDCs govern angiogenesis and migration by acting as co-receptors of growth factor signals and have recently been recognized as biomarkers of stemness in breast cancer [ 17 , 51 , 52 ]. Finally, CD44 is also implicated as a marker for the induction of cancer stem cell (CSC) phenotype and thus, the therapeutic resistance in various cancers [ 53 , 54 ].…”