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

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          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.

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          Most cited references311

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          A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.

          A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.
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            An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.

            Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor-positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers. Unlike AKT1 mutations that were absent from cell lines, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant effect on outcome after adjuvant tamoxifen therapy in 157 hormone receptor-positive breast cancer patients. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines. PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss rendered cells significantly more sensitive to growth inhibition by the PI3K inhibitor LY294002 than did PIK3CA mutations. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration present may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.
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              Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2.

              BRCA2 mutations predispose carriers to breast and ovarian cancer and can also cause other cancers and Fanconi anemia. BRCA2 acts as a "caretaker" of genome integrity by enabling homologous recombination (HR)-based, error-free DNA double-strand break repair (DSBR) and intra-S phase DNA damage checkpoint control. Described here is the identification of PALB2, a BRCA2 binding protein. PALB2 colocalizes with BRCA2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions. In addition, multiple, germline BRCA2 missense mutations identified in breast cancer patients but of heretofore unknown biological/clinical consequence appear to disrupt PALB2 binding and disable BRCA2 HR/DSBR function. Thus, PALB2 licenses key cellular biochemical properties of BRCA2 and ensures its tumor suppression function.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                July 2014
                12 July 2014
                : 5
                : 13
                : 4603-4650
                Affiliations
                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
                Author notes
                Correspondence to: James A. McCubrey, mccubreyj@ 123456ecu.edu
                Article
                10.18632/oncotarget.2209
                4148087
                25051360
                61f7ade0-0227-4e9c-9ea0-5009021fe608
                Copyright: © 2014 Davis et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 June 2014
                : 11 July 2014
                Categories
                Review

                Oncology & Radiotherapy
                targeted therapy,therapy resistance,mutations,pi3k,mtor,rapamycin
                Oncology & Radiotherapy
                targeted therapy, therapy resistance, mutations, pi3k, mtor, rapamycin

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