title: Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer.
abstract: The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) network plays a key regulatory function in cell survival, proliferation, migration, metabolism, angiogenesis, and apoptosis. Genetic aberrations found at different levels, either with activation of oncogenes or inactivation of tumor suppressors, make this pathway one of the most commonly disrupted in human breast cancer. The PI3K-dependent phosphorylation and activation of the serine/threonine kinase AKT is a key activator of cell survival mechanisms. The activation of the oncogene PIK3CA and the loss of regulators of AKT including the tumor suppressor gene PTEN are mutations commonly found in breast tumors. AKT relieves the negative regulation of mTOR to activate protein synthesis and cell proliferation through S6K and 4EBP1. The common activation of the PI3K pathway in breast cancer has led to the development of compounds targeting the effector mechanisms of the pathway including selective and pan-PI3K/pan-AKT inhibitors, rapamycin analogs for mTOR inhibition, and TOR-catalytic subunit inhibitors. The influences of other oncogenic pathways such as Ras-Raf-Mek on the PI3K pathway and the known feedback mechanisms of activation have prompted the use of compounds with broader effect at multiple levels and rational combination strategies to obtain a more potent antitumor activity and possibly a meaningful clinical effect. Here, we review the biology of the network, its role in the development and progression of breast cancer, and the evaluation of targeted therapies in clinical trials.
authors.affiliation: Department of Internal Medicine, University of Miami Miller School of Medicine at FAU, West Palm Beach, Florida, USA.
authors.forename: Leonel F
authors.initials: LF
authors.lastname: Hernandez-Aya
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gonzalez-Angulo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human