title: Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer.
abstract: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated.
  
  
  
  One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively.
  
  
  
  Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression.
  
  
  
  Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC.
authors.affiliation: Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.|Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA.|Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Qing-Bai
authors.initials: QB
authors.lastname: She
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences, Lund University, Lund, Sweden.|Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
authors.forename: Sofia K
authors.initials: SK
authors.lastname: Gruvberger-Saal
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.|Department of Medicine, Columbia University, New York, NY, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Maurer
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Yilun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology, Seinäjoki Central Hospital, Seinäjoki, Finland.
authors.forename: Mervi
authors.initials: M
authors.lastname: Jumppanen
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
authors.forename: Meaghan
authors.initials: M
authors.lastname: Dendy
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
authors.forename: Ying-Ka Ingar
authors.initials: YK
authors.lastname: Lau
authors.affiliation: Department of Experimental Oncology, Mediterranean Institute of Oncology, Catania, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Memeo
authors.affiliation: Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Horlings
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: van de Vijver
authors.affiliation: Institute of Medical Technology, University of Tampere, Tampere, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Isola
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.|Department of Pathology, Columbia University, New York, NY, USA.
authors.forename: Hanina
authors.initials: H
authors.lastname: Hibshoosh
authors.affiliation: Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.|Department of Medicine, Columbia University, New York, NY, USA.|Department of Pathology, Columbia University, New York, NY, USA.|Department of Oncological Sciences and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ramon
authors.initials: R
authors.lastname: Parsons
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences, Lund University, Lund, Sweden. lao.saal@med.lu.se.|Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA. lao.saal@med.lu.se.|Translational Oncogenomics Unit, Division of Oncology and Pathology, Lund University Cancer Center, Medicon Village 404-B2, SE-22381, Lund, Sweden. lao.saal@med.lu.se.
authors.forename: Lao H
authors.initials: LH
authors.lastname: Saal
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D046888:Tissue Array Analysis / Q000379:methods; D023041:Xenograft Model Antitumor Assays
chemical_list: D000730:Androstadienes; D002867:Chromones; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C509268:pegylated 17-hydroxywortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011092:Polyethylene Glycols; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077156:Gefitinib
keywords: Basal-like; Breast cancer; Combination therapy; EGFR; PTEN