Biomedical Laboratory Techniques

Biomedical Laboratory Techniques



Biomedical Laboratory Techniques

Introduction

Breast cancer is the most common malignancy worldwide and the second leading cause of cancer death in women in USA and the first one in Argentina . In the past decades, the development of strategies for breast cancer treatment focused on understanding the expression, regulation, and function of critical signaling pathways involved in cancer initiation and progression and allowed the identification of breast cancer subsets with different biology . One of the most important targeted therapies has been the use of the antihuman epidermal growth factor receptor 2 (HER2) for tumors overexpressing this receptor .Breast cancer is a heterogeneous disease that can be classified in different subsets with distinct biology and molecular profiles , some of which can be associated with enhanced tumor aggressiveness and poor clinical outcome (Gideon, 2003, p.1925).

Breast tumors vary according to the expression of estrogen receptor (ER), progesterone receptor (PR), and amplification of HER2 which is overexpressed in approximately 20% to 25% of invasive breast cancers . The resulting subgroups are important not only for clinical behaviour and prognosis, but also for predictive response to targeted therapies against these receptors and the pathways they activate.The HER2/neu gene encodes a 185-kDA transmembrane tyrosine kinase (TK) receptor that belongs to the EGF receptor (EGFR) family which consists of EGFR/ErbB1 (HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). All receptors, with the exception of HER3, contain a cytoplasmatic TK region and all, with the exception of HER2, bind specific ligands via extracellular domains. Upon ligand binding, receptors dimerize using HER2 as their preferential binding partner . These receptors are expressed in a variety of tissues of epithelial, mesenchymal, and neuronal origin (Kenneth, 2002, p.422).

Activation of the HER receptors under physiological conditions is controlled by spatial and temporal expression of their ligands, members of the EGF family of growth factors. Homo- or heterodimerization of receptors after ligand binding results in the phosphorylation of residues from the intracellular domain of the receptor, resulting in the recruitment of signaling molecules from the cytoplasm and the initiation of several signaling pathways. HER2 dimerization triggers diverse cellular processes related to enhanced cell motility, survival, and proliferation as well as resistance to apoptosis . Certain pathways are preferentially modulated by different receptors due to the ability of each receptor to bind specific effector proteins.

Two of the main activated pathways are RAS/Raf/MAPK and the phosphatidylinositol 3-kinase (PI3K)-Akt pathways .Overexpression of HER2 enables constitutive activation of growth factor signaling pathways, serving as oncogenic drivers in breast cancer. It is well known that cancer patients whose tumors have alterations in HER receptors tend to have a more aggressive disease associated with predictive factors of a poor clinical outcome . Constitutive EGFR activation can be elicited by EGF-related growth factors produced either by the tumor cells themselves or by the surrounding stromal cells (Barry, 2003, p.160).

HER2 as Target for Cancer Therapy

Amplification of HER2 was originally detected in a subset of breast tumours as well as in gastric , ...