*3.4. EGFR Pathway*

EGFR (epidermal growth factor receptor) is a plasma membrane protein that is characterized by an intracellular region acting as tyrosine kinase and an extracellular receptor domain. The dysregulation of EGFR expression has been associated with cellular neoplastic transformation. EGCG interaction with EGFR was demonstrated and described in its mechanism. EGCG binds to a specific laminin receptor whose expression is reported in a variety of tumor cells: this connection can interfere with the activity of the kinase-phosphatase cascades [72]. The laminin receptor has been recently related to MAPK signaling in human melanoma metastasis mechanism [73]. EGCG inhibition of EGFR and HER2 was demonstrated in colon cancer cells line (HT29), in which these proteins are overexpressed in comparison with normal tissue. EGCG at 20 μg/mL resulted in cell growth reduction, cell cycle arrest in G1 phase, and apotosis induction by the activation of caspase-3 and -9, with critical impact on EGFR/ERK and EGFR/Akt signaling pathways [74]. The adjuvant e ffect of EGFR in breast cancer treatment was demonstrated in di fferent cell lines (MCF-7, MCF-7TAM, and MDA-MB-231). The combined treatment of EGCG with IIF (6-OH-11-O-hydroxyphenanthrene) reduced the invasive phenotype and up-regulated the expression of molecules that are involved in the invasion process, again acting on EGFR/Akt pathway and their regulated targets, such as CD44, extracellular matrix metalloproteinases inducer (EMMPRIN), matrix metalloproteinases, and tissue inhibitor of metalloproteinases (TIMPs) [75]. Similarly EGCG activity was also investigated in MCF-7tam (a breast carcinoma cell line resistant to the chemoagent tamoxifen), where EGCG was demonstrated to reduce the resistance to Tamoxifen and block cell growth and invasion [76]. In this last work, the EGFR/ERK pathway was downregulated, with e ffects on matrix metalloproteinase-2 and -9, EMMPRIN. It emerges as the e ffects EGCG on EGFR pathway depend on cancer cell type and sugges<sup>t</sup> as EGCG can have an adjuvant role in EGFR targeted therapy approach.
