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Integrated molecula...
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She, Qing BaiMemorial Sloan-Kettering Cancer Center,University of Kentucky
(author)
Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer
- Article/chapterEnglish2016
Publisher, publication year, extent ...
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2016-08-02
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Springer Science and Business Media LLC,2016
Numbers
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LIBRIS-ID:oai:lup.lub.lu.se:ddd51ef5-fed0-4da5-bebe-fced0b49c006
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https://lup.lub.lu.se/record/ddd51ef5-fed0-4da5-bebe-fced0b49c006URI
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https://doi.org/10.1186/s12885-016-2609-2DOI
Supplementary language notes
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Language:English
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Summary in:English
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Classification
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
Notes
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Background: 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. Methods: 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. Results: 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. Conclusions: 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.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Gruvberger, SofiaLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)onk-sgu
(author)
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Maurer, MatthewColumbia University
(author)
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Chen, YilunLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)med-yic
(author)
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Jumppanen, MerviSouth Ostrobothnia Central Hospital
(author)
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Su, TaoColumbia University
(author)
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Dendy, MeaghanColumbia University
(author)
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Lau, Ying Ka IngarColumbia University
(author)
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Memeo, LorenzoMediterranean Institute of Oncology
(author)
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Horlings, Hugo M.Netherlands Cancer Institute
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van de Vijver, Marc J.Academic Medical Center of University of Amsterdam (AMC)
(author)
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Isola, JormaUniversity of Tampere(Swepub:lu)onk-jis
(author)
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Hibshoosh, HaninaColumbia University
(author)
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Rosen, NealMemorial Sloan-Kettering Cancer Center
(author)
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Parsons, RamonIcahn School of Medicine at Mount Sinai,Columbia University
(author)
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Saal, Lao H.Lund University,Lunds universitet,Kliniska Vetenskaper, Helsingborg,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Clinical Sciences, Helsingborg,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine,Columbia University(Swepub:lu)onk-ls0
(author)
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Memorial Sloan-Kettering Cancer CenterUniversity of Kentucky
(creator_code:org_t)
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In:BMC Cancer: Springer Science and Business Media LLC16:11471-2407
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