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Profiling phospho-signaling networks in breast cancer using reverse-phase protein arrays
T S Gujral1, R L Karp, A Finski
1Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
Oncogene
|September 5, 2012
Summary
Reverse Phase Protein Arrays (RPPAs) profiled breast cancer signaling pathways, revealing Axl and cMet receptor tyrosine kinase (RTK) cross-talk. This discovery suggests dual-receptor inhibitors may improve breast cancer treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cell signaling pathway analysis in tumors aids oncogenesis understanding and biomarker identification.
- Reverse Phase Protein Arrays (RPPAs) are used for proteomic profiling but measuring phosphorylation changes remains challenging.
Purpose of the Study:
- To profile signaling proteins in breast cancer using RPPAs.
- To investigate the functional link between Axl and cMet receptor tyrosine kinases (RTKs) in breast cancer.
- To explore potential therapeutic strategies based on RTK interactions.
Main Methods:
- RPPA technology was employed to analyze signaling proteins in 56 breast cancer and matched normal tissue samples.
- Well-validated antibodies and repeat deposition were used to monitor protein phosphorylation patterns.
- In vitro studies involving protein depletion and overexpression in a triple-negative breast cell line were conducted to elucidate RTK cross-talk.
Main Results:
- RPPA analysis revealed distinct phosphorylation patterns consistent with breast cancer classification and oncogenesis.
- A novel functional cross-talk was identified between Axl and cMet RTKs, involving Axl-mediated cMet modification and cMet's role in Gas6-Axl signaling.
- Physical interaction between Axl and cMet was also suggested.
Conclusions:
- The identified cross-talk between Axl and cMet RTKs in breast cancer has significant implications for understanding oncogenesis and drug resistance.
- Bi-specific receptor inhibitors targeting both Axl and cMet may offer greater therapeutic efficacy compared to current mono-specific antibody approaches.
