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Integrated molecula...
Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer
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- She, Qing Bai (author)
- Memorial Sloan-Kettering Cancer Center,University of Kentucky
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- Gruvberger, Sofia (author)
- Lund 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
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- Maurer, Matthew (author)
- Columbia University
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- Chen, Yilun (author)
- Lund 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
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- Jumppanen, Mervi (author)
- South Ostrobothnia Central Hospital
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- Su, Tao (author)
- Columbia University
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- Dendy, Meaghan (author)
- Columbia University
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- Lau, Ying Ka Ingar (author)
- Columbia University
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- Memeo, Lorenzo (author)
- Mediterranean Institute of Oncology
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- Horlings, Hugo M. (author)
- Netherlands Cancer Institute
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- van de Vijver, Marc J. (author)
- Academic Medical Center of University of Amsterdam (AMC)
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- Isola, Jorma (author)
- University of Tampere
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- Hibshoosh, Hanina (author)
- Columbia University
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- Rosen, Neal (author)
- Memorial Sloan-Kettering Cancer Center
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- Parsons, Ramon (author)
- Icahn School of Medicine at Mount Sinai,Columbia University
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- Saal, Lao H. (author)
- 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
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(creator_code:org_t)
- 2016-08-02
- 2016
- English.
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 16:1
- Related links:
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http://dx.doi.org/10... (free)
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https://bmccancer.bi...
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Abstract
Subject headings
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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
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- Basal-like
- Breast cancer
- Combination therapy
- EGFR
- PTEN
Publication and Content Type
- art (subject category)
- ref (subject category)
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BMC Cancer
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To the university's database
- By the author/editor
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She, Qing Bai
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Gruvberger, Sofi ...
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Maurer, Matthew
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Chen, Yilun
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Jumppanen, Mervi
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Su, Tao
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show more...
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Dendy, Meaghan
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Lau, Ying Ka Ing ...
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Memeo, Lorenzo
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Horlings, Hugo M ...
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van de Vijver, M ...
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Isola, Jorma
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Hibshoosh, Hanin ...
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Rosen, Neal
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Parsons, Ramon
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Saal, Lao H.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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BMC Cancer
- By the university
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Lund University