Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention
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Nicole M. Davis1, Melissa Sokolosky1, Kristin Stadelman1, Stephen L. Abrams1, Massimo Libra2, Saverio Candido2, Ferdinando Nicoletti2, Jerry Polesel3, Roberta Maestro4, Antonino D’Assoro5, Lyudmyla Drobot6, Dariusz Rakus7, Agnieszka Gizak7, Piotr Laidler8, Joanna Dulińska-Litewka8, Joerg Basecke9, Sanja Mijatovic10, Danijela Maksimovic-Ivanic10, Giuseppe Montalto11,12, Melchiorre Cervello12, Timothy L. Fitzgerald13, Zoya N. Demidenko14, Alberto M. Martelli15, Lucio Cocco15, Linda S. Steelman1 and James A. McCubrey1
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
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
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.
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