Transcriptomics

Dataset Information

44

Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer.


ABSTRACT: Abstract 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. Gene expression profiles were generated for 95 breast tumors using Agilent Human 44K v5 microarrays following the manufacturer protocol. Stratagene Universal Human Reference RNA was used as the common control sample.

ORGANISM(S): Homo sapiens  

SUBMITTER: Tao Su   Mervi Jumppanen  Ying-Ka I Lau  Jorma Isola  Neal Rosen  Sofia K Gruvberger-Saal  Matthew Maurer  Yilun Chen  Hugo M Horlings  Meaghan Dendy  Hanina Hibshoosh  Qing-Bai She  Lao H Saal  Lorenzo Memeo  Marc J van de Vijver  Ramon Parsons 

PROVIDER: E-GEOD-74667 | ArrayExpress | 2016-08-21

SECONDARY ACCESSION(S): GSE74667PRJNA301129

REPOSITORIES: GEO, ArrayExpress

altmetric image

Publications

Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer.

She Qing-Bai QB   Gruvberger-Saal Sofia K SK   Maurer Matthew M   Chen Yilun Y   Jumppanen Mervi M   Su Tao T   Dendy Meaghan M   Lau Ying-Ka Ingar YK   Memeo Lorenzo L   Horlings Hugo M HM   van de Vijver Marc J MJ   Isola Jorma J   Hibshoosh Hanina H   Rosen Neal N   Parsons Ramon R   Saal Lao H LH  

BMC cancer 20160802


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 relate  ...[more]

Similar Datasets

2008-12-03 | GSE13787 | GEO
| GSE59800 | GEO
| GSE80667 | GEO
| PRJNA110619 | ENA
| GSE53300 | GEO
2019-09-30 | BIOMD0000000827 | BioModels
2007-04-07 | GSE5325 | GEO
| PRJNA301129 | ENA
| GSE68114 | GEO
| GSE68117 | GEO