Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention

Abstract

// Nicole M. Davis 1 , Melissa Sokolosky 1 , Kristin Stadelman 1 , Stephen L. Abrams 1 , Massimo Libra 2 , Saverio Candido 2 , Ferdinando Nicoletti 2 , Jerry Polesel 3 , Roberta Maestro 4 , Antonino D’Assoro 5 , Lyudmyla Drobot 6 , Dariusz Rakus 7 , Agnieszka Gizak 7 , Piotr Laidler 8 , Joanna Dulińska-Litewka 8 , Joerg Basecke 9 , Sanja Mijatovic 10 , Danijela Maksimovic-Ivanic 10 , Giuseppe Montalto 11,12 , Melchiorre Cervello 12 , Timothy L. Fitzgerald 13 , Zoya N. Demidenko 14 , Alberto M. Martelli 15 , Lucio Cocco 15 , Linda S. Steelman 1 and James A. McCubrey 1 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858 USA 2 Department of Bio-Medical Sciences, University of Catania, Catania, Italy 3 Unit of Epidemiology and Biostatistics, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy 4 Experimental Oncology 1, CRO IRCCS, National Cancer Institute, Aviano, Pordenone, Italy 5 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA 6 Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine 7 Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland 8 Chair of Medical Biochemistry, Jagiellonian University Medical College, Kraków, Poland 9 Department of Medicine University of Göttingen, Göttingen, Germany 10 Department of Immunology, Institute for Biological Research “Sinisa Stankovic” University of Belgrade, Belgrade, Serbia 11 Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy 12 Consiglio Nazionale delle Ricerche,Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy 13 Department of Surgery, Brody School of Medicine at East Carolina University, Greenville, NC 14 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA 15 Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy Correspondence: James A. McCubrey, email: // Keywords : Targeted Therapy, Therapy Resistance, Mutations, PI3K, mTOR, rapamycin Received : June 04, 2014 Accepted : July 11, 2014 Published : July 12, 2014 Abstract The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2 , ER alpha, BRCA1, BRCA2, EGFR1 , PIK3CA , PTEN , TP53 , RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway ( e.g. , PIK3CA ) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstream HER2 has been associated with breast cancer initiating cells (CICs) and in some cases resistance to treatment. The anti-diabetes drug metformin can suppress the growth of breast CICs and herceptin-resistant HER2+ cells. This review will discuss the importance of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but will also include relevant examples from other cancer types. The targeting of this pathway will be discussed as well as clinical trials with novel small molecule inhibitors. The targeting of the hormone receptor, HER2 and EGFR1 in breast cancer will be reviewed in association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway.