HER2 also activates the Akt growth pathway in these stem cells . 3. diagnosed in 2008 in the United States alone . Over 40,000 of these diagnosed Daphnetin cases resulted in death, mostly in women . BC in women is the most commonly diagnosed cancer that accounts for 26% of all new cancer cases . Well-known growth signaling pathways contribute to generation and progression of BC among other cancer types by promoting cell growth and proliferation . 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 usually 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 usually 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 Rabbit Polyclonal to ALK this resistance. 2. HER2 Receptor The HER/EGF family of receptors consists of four cell-surface receptors named HER1 (erbB1), HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4) [4, 5]. These receptors are involved in cell growth, differentiation, and survival. They are activated by a ligand that causes heterodimerization of these receptors so that a cascade of phosphorylation and signal transduction events is initiated leading to transcription of specific genes involved in cell proliferation and survival . Receptor dimers that contain HER2 produce stronger and more prolonged signal transduction event than those dimmers formed by other HER receptors [4C6]. The gene encoding HER2/neu (erbB2) is usually a protooncogene located in chromosome 17q21 and encodes a 185-kD transmembrane glycoprotein with tyrosine kinase activity [4, 5]. HER2 intracellular domain name has a terminal carboxy segment autophosphorylation of which transmits the extracellular signal into an intracellular signal transduction event. In 20C30% of breast cancer tumors, the HER2 receptor is usually either amplified, overexpressed, or undergoes both events [4, 7]. Receptor overexpression is generally due to gene amplification, with one study reporting up to a 25-fold increase in HER2 copy number . Tumors with HER2 overexpression generally have a poor disease-free survival [9, 10]. High levels of HER2 have strong correlations with the pathogenesis, and prognosis of breast cancer [11, 12]. Overexpression of the HER2 protein is usually detectable both in the primary tumors and in metastatic sites  indicating the effectiveness of anti-HER2 therapy in all disease locations. HER2 is distinguished from other HER family members by lack of a natural ligand which makes the molecule a suitable therapeutic candidate. In addition, a strong correlation exists between HER2 levels and carcinogenesis [14, 15]. High levels of HER2 found in cancer cell membranes compared to those of normal cells and HER2 expression in both primary tumors and metastatic sites have made HER2 inhibitors important for breast cancer therapy [16, 17]. Research on stem cells as the initiators of breast cancer development has elucidated the status and function of the HER2 receptors in BC stem cells (BCSCs). Studies on patient samples show a significant correlation between HER2 overexpression and the expression of aldehyde dehydrogenase 1 (ALDH1) a key marker for BCSCs . HER2 overexpression also acts as a driving force for breast stem cell malignancy, mammary tumorigenesis and invasion . Epithelial cells isolated from normal breast form mammospheres that are nonadherent and spherical morphologies . Daphnetin HER2 overexpression increases mammosphere formation by BCSCs . Generation of mammospheres is an indication of increased self-renewal in these stem cells, whereas the size of these colonies that indicates proliferation of progenitors is also increased by HER2. The report by Korkaya and coworkers indicates that HER2 not only increases stem-cell number but also upregulates the expression of stem Daphnetin cell-related genes including Oct3/4, Nothc1, Notch2, Jag1, Gli1 in Aldefluor+ cells. HER2 also activates the Akt growth pathway in these stem cells . 3. HER2-ER Crosstalks Crosstalks between BC cell receptors are important for full implementation of their biological activities. HER2 interacts with ER in a variety of approaches. Estradiol as an ER ligand induces a signal transduction cascade that trans-activates.