Система инсулиноподобных факторов роста и рак молочной железы

Рассмотрены множественное воздействие на ИФР-сигнальный путь, в частности, редукцию и нейтрализацию ИФР-лиганда, подавляющую регуляцию и конкурентное связывание с ИФР-рецептором, а также развитие ИФР-независимых антагонистических стратегий.

IGF System and Breast Cancer

IGF system includes receptors and binding proteins, which form a complex regulated network of interactions, both among themselves and with other biological growth regulators and cell survival. Cellular effects of IGF are mediated by two types of specific IGF receptors, and insulin receptors, and hybrid receptor binds both insulin and IGF-1. IGF receptor 1 type (IGF-1R) is a glycosylated heterotetramer consisting of two extracellular α-subunits and two transmembrane β-subunits with the internal tyrosine kinase activity. Binding of IGF-1R with corresponding ligands leads to its oligomerization, autophosphorylation and activation of the internal tyrosine kinase. Then, IGF-1R tyrosine kinase phosphorylates the variety of cell substrates and signaling molecules involved in the regulation of apoptosis, the construction of the cytoskeleton and cell adhesion processes, as well as many other physiological processes in cells. IGF receptor type 2 (IGF-2R) is a cation-independent mannose 6-phosphate receptor and its role in the effects of IGF is still unclear. IGF-R1 is a mediator of the primary response of IGF, is expressed in all cell types except hepatocytes and T-lymphocytes, and serves as an important element of the normal growth and organism development. IGF signaling pathway is involved in the activation of the mitogen-activated protein kinases cascade and the signaling cascade. Key components of this system are the phosphatidylinositol 3-kinase (PI-3K) and protein kinase serine-threonine Akt. Activation of the mitogen-activated protein kinases cascade leads eventually to the inhibition of apoptosis and stimulation of cell proliferation. Circulating IGF binds with the high affinity binding proteins (IGFBP). Currently we know six different IGFBPs, as well as a family of homologous binding proteins, which have lower affinity for IGF-ligands. IGFBP modulate the bioavailability and activity of IGF in various ways. In the mammary gland IGF-1 is found mainly in the normal stromal cells, IGF-2 is also determined mainly in stromal cells, but can be detected in malignant breast epithelium. The high level of IGF-2 expression is associated with poor prognosis in breast cancer, and increased levels of IGF-1 in blood serum are an independent risk factor for breast cancer in premenopausal women. Since the action of IGF-1 and estrogen is correlated, we can assume that inhibition of both systems simultaneously may be more effective for the treatment of breast cancer than blocking each system separately. As a target for antitumor therapy could be perspective to try multiple action on IGF signaling pathway, including reduction and neutralization of IGF ligand, which downregulates IGF binding to receptors, and also developing of IGF independent antagonistic strategies.