title: Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention.
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, ERalpha, 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.
authors: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858 USA.
authors: Nicole M
authors: NM
authors: Davis
authors: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858 USA.
authors: Melissa
authors: M
authors: Sokolosky
authors: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858 USA.
authors: Kristin
authors: K
authors: Stadelman
authors: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858 USA.
authors: Steve L
authors: SL
authors: Abrams
authors: Department of Bio-Medical Sciences, University of Catania, Catania, Italy.
authors: Massimo
authors: M
authors: Libra
authors: Department of Bio-Medical Sciences, University of Catania, Catania, Italy.
authors: Saverio
authors: S
authors: Candido
authors: Department of Bio-Medical Sciences, University of Catania, Catania, Italy.
authors: Ferdinando
authors: F
authors: Nicoletti
authors: Unit of Epidemiology and Biostatistics, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
authors: Jerry
authors: J
authors: Polesel
authors: Experimental Oncology 1, CRO IRCCS, National Cancer Institute, Aviano, Pordenone, Italy.
authors: Roberta
authors: R
authors: Maestro
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: Antonino
authors: A
authors: D'Assoro
authors: Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors: Lyudmyla
authors: L
authors: Drobot
authors: Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland.
authors: Dariusz
authors: D
authors: Rakus
authors: Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland.
authors: Agnieszka
authors: A
authors: Gizak
authors: Chair of Medical Biochemistry, Jagiellonian University Medical College, Kraków, Poland.
authors: Piotr
authors: P
authors: Laidler
authors: Chair of Medical Biochemistry, Jagiellonian University Medical College, Kraków, Poland.
authors: Joanna
authors: J
authors: Dulińska-Litewka
authors: Department of Medicine University of Göttingen, Göttingen, Germany.
authors: Joerg
authors: J
authors: Basecke
authors: Department of Immunology, Institute for Biological Research "Sinisa Stankovic" University of Belgrade, Belgrade, Serbia.
authors: Sanja
authors: S
authors: Mijatovic
authors: Department of Immunology, Institute for Biological Research "Sinisa Stankovic" University of Belgrade, Belgrade, Serbia.
authors: Danijela
authors: D
authors: Maksimovic-Ivanic
authors: Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy; Consiglio Nazionale delle Ricerche,Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy.
authors: Giuseppe
authors: G
authors: Montalto
authors: Consiglio Nazionale delle Ricerche,Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy.
authors: Melchiorre
authors: M
authors: Cervello
authors: Department of Surgery, Brody School of Medicine at East Carolina University, Greenville, NC.
authors: Timothy L
authors: TL
authors: Fitzgerald
authors: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Zoya
authors: Z
authors: Demidenko
authors: Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.
authors: Alberto M
authors: AM
authors: Martelli
authors: Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.
authors: Lucio
authors: L
authors: Cocco
authors: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858 USA.
authors: Linda S
authors: LS
authors: Steelman
authors: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858 USA.
authors: James A
authors: JA
authors: McCubrey
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C484760:PIK3CA protein, human; C494929:PTEN protein, human