title: Rac signaling in breast cancer: a tale of GEFs and GAPs.
abstract: Rac GTPases, small G-proteins widely implicated in tumorigenesis and metastasis, transduce signals from tyrosine-kinase, G-protein-coupled receptors (GPCRs), and integrins, and control a number of essential cellular functions including motility, adhesion, and proliferation. Deregulation of Rac signaling in cancer is generally a consequence of enhanced upstream inputs from tyrosine-kinase receptors, PI3K or Guanine nucleotide Exchange Factors (GEFs), or reduced Rac inactivation by GTPase Activating Proteins (GAPs). In breast cancer cells Rac1 is a downstream effector of ErbB receptors and mediates migratory responses by ErbB1/EGFR ligands such as EGF or TGFα and ErbB3 ligands such as heregulins. Recent advances in the field led to the identification of the Rac-GEF P-Rex1 as an essential mediator of Rac1 responses in breast cancer cells. P-Rex1 is activated by the PI3K product PIP3 and Gβγ subunits, and integrates signals from ErbB receptors and GPCRs. Most notably, P-Rex1 is highly overexpressed in human luminal breast tumors, particularly those expressing ErbB2 and estrogen receptor (ER). The P-Rex1/Rac signaling pathway may represent an attractive target for breast cancer therapy.
authors: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
authors: Eva
authors: E
authors: Wertheimer
authors: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
authors: Alvaro
authors: A
authors: Gutierrez-Uzquiza
authors: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
authors: Cinthia
authors: C
authors: Rosemblit
authors: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
authors: Cynthia
authors: C
authors: Lopez-Haber
authors: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
authors: Maria Soledad
authors: MS
authors: Sosa
authors: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA. Electronic address: marcelog@upenn.edu.
authors: Marcelo G
authors: MG
authors: Kazanietz
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002450:Cell Communication; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D020880:Neuregulins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D020880:Neuregulins; D043562:Receptors, G-Protein-Coupled; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D020744:rac GTP-Binding Proteins