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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Mar 22, 2019 |
| Title |
E-cadherin loss induces autocrine activation of oncogenic growth factor signalling in metastatic lobular breast cancer. |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Background: Despite the fact that loss of E-cadherin is causal to the development and progression of invasive lobular breast cancer (ILC), no targeted therapy is available to treat this major breast cancer subtype. This study is aimed at identifying clinically targetable pathways that are aberrantly active downstream of E-cadherin loss in ILC.
Methods: Reverse-phase protein array (RPPA) analyses were performed in the context of E-cadherin loss using mouse and human breast cancer cells. A combination of mRNA sequencing, conditioned medium growth assays and CRISPR-Cas9 knock-out experiments were performed to identify and validate activation of oncogenic pathways in ILC. Human ILC samples were employed to validate activation by immunohistochemistry on tissue micro-arrays. Finally, we assessed the effect of pathway inhibition using anoikis resistance and anchorage-dependent growth in vitro.
Results: We demonstrate that E-cadherin loss leads to increased activation of FAK and PI3K/AKT signalling. Autocrine activation of growth factor receptor signalling and its downstream PI3K/AKT hub was a direct consequence of E-cadherin loss, independent of activating mutations in either PIK3CA, AKT or PTEN. Analysis of human ILC samples confirmed pathway activity, and pharmacological inhibition of AKT using AZD5363 and MK2206 resulted in robust inhibition of cell growth and survival of ILC cells in anchorage-dependent and independent conditions. Moreover, our results indicate a role for intracellular FAK in the regulation of ILC anoikis resistance.
Conclusion: Our data demonstrate that E-cadherin loss evokes additional PI3K/AKT activation independent of oncogenic mutations in this pathway. We propose clinical intervention of PI3K/AKT in ILC based on functional E-cadherin inactivation, irrespective of activating pathway mutations.
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| Overall design |
Expression profiling (RNA-seq) of mouse (mILC-1, mILC-2) and human (IPH-926) invasive lobular carcinoma cell lines in adherent and suspension cell culture conditions.
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| Contributor(s) |
Tenhagen M, Teo K, ter Hoeve N, Strengman E, Byron A, Mandoli A, Sotoca AM, Singh AA, Martens JH, Stunnenberg HG, Christgen M, van Diest PJ, Brunton VG, Derksen PW |
| Citation(s) |
30337563 |
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| Submission date |
May 27, 2016 |
| Last update date |
Nov 11, 2021 |
| Contact name |
Joost Martens |
| E-mail(s) |
j.martens@science.ru.nl
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| Phone |
0243780645
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| Organization name |
Radboud University
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| Department |
RIMLS
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| Lab |
Molecular Biology
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| Street address |
Geert Grooteplein 28
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| City |
Nijmegen |
| State/province |
Nederland |
| ZIP/Postal code |
6525GA |
| Country |
Netherlands |
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| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA323547 |
| SRA |
SRP075807 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE81977_RAW.tar |
31.1 Mb |
(http)(custom) |
TAR (of WIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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