EGFR is a pivotal player of the E2/ERß - mediated functional properties, aggressiveness, and stemness in triple-negative breast cancer cells.

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 (ERß) interplay in the regulation of invasion and cell-matrix interactions. In this study, we report on the EGFR-ERß functional relationship in connection to the aggressiveness and cancer stem cell (CSC)-like characteristics of TNBC cells. ERß-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 ERß-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 ERß-dependent way in TNBC.

Advances in targeting epidermal growth factor receptor signaling pathway in mammary cancer.

Breast cancer is the most common malignancy among women worldwide. The role of epidermal growth factor receptor (EGFR) in many epithelial malignancies has been established, since it is dysregulated, overexpressed or mutated. Its overexpression has been associated with increased aggressiveness and metastatic potential in breast cancer. The well-established interplay between EGFR signaling pathway and estrogen receptors (ERs) as well as major extracellular matrix (ECM) mediators is crucial for regulating basic functional properties of breast cancer cells, including migration, proliferation, adhesion and invasion. EGFR activation leads to endocytosis of the receptor with implications in the regulation of downstream signaling effectors, the modulation of autophagy and cell survival. Therefore, EGFR is considered as a promising therapeutic target in breast cancer. Several anti-EGFR therapies (i.e. monoclonal antibodies and tyrosine kinase inhibitors) have been evaluated both in vitro and in vivo, making their way to clinical trials. However, the response rates of anti-EGFR therapies in the clinical trials is low mainly due to chemoresistance. Novel drug design, phytochemicals and microRNAs (miRNAs) are assessed as new therapeutic approaches against EGFR. The main goal of this review is to highlight the importance of targeting EGFR signaling pathway in terms of its crosstalk with ERs, the involvement of ECM effectors and epigenetics. Moreover, recent insights into the design of specialized delivery systems contributing in the development of novel diagnostic and therapeutic approaches in breast cancer are addressed.