Epidermal growth factor (EGF) family of receptors is involved in cell growth and differentiation. The human EGF2 (HER2) lacks natural ligands, and correlation between HER2 levels and carcinogenesis makes the receptor an ideal candidate for targeted therapy in breast cancer. Trastuzumab is a humanized antibody applied against HER2-positive breast tumors in clinic. Metastatic tumors respond well to trastuzumab therapy for the first year, but development of antibody resistance helps the tumors to regrow allowing the disease to progress. Trastuzumab resistance is shaped via a range of intracellular signaling pathways that are interconnected and share in key effector molecules. Identification of a common node central to these resistance pathways could provide an ultimate solution for trastuzumab resistance in breast and other cancers. 1. Introduction Breast cancer (BC) originates from the epithelial cells of the breast tissue that line the terminal duct lobular unit. BC is the most common cancer type that affects world population. More than 180,000 new cases of BC were diagnosed in 2008 in the United States alone [1]. Over 40,000 of these diagnosed cases resulted in death, mostly in women [1]. BC in women is the most commonly diagnosed cancer that accounts for 26% of all new cancer cases [2]. Well-known growth signaling pathways contribute to generation and progression of BC among other cancer types by promoting cell growth and proliferation [3]. These signaling pathways are promoted by a number of membrane-bound and intracellular receptors. The gene expression and biological activities of these receptors may have great impact on BC tumor initiation, progression, relapse, and prevention or treatment. Estrogen receptor (ER), progesterone receptor (PR), rearranged during transfection (RET), and human epidermal growth factor 2 (HER2) are the main membrane-bound receptors playing key roles in BC. Hormone therapy is directed against ER that is expressed in 70% of BC tumors. Antibody therapy, on the other hand, was initiated with development of trastuzumab (TZMB) that specifically targets HER2 in 20 to 30% of BC cases where HER2 is strongly present. Resistance to hormone therapy and TZMB therapy are two major hurdles in current clinical BC therapy. In this paper, we will focus on the main causative sources of TZMB therapy and recent developments in exploration of key molecules that hold promise for eradication of this resistance. 2. HER2 Receptor The HER/EGF family of receptors consists of four cell-surface receptors named HER1 (erbB1), HER2 (erbB2), HER3 (erbB3),
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