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Flotillin depletion affects ErbB protein levels in different human breast cancer cells
Nagham Asp1, Sascha Pust1, Kirsten Sandvig2
1Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway.
Abstract:
The ErbB3 receptor is an important regulator of cell growth and carcinogenesis. Among breast cancer patients, up to 50-70% have ErbB3 overexpression and 20-30% show overexpressed or amplified ErbB2. ErbB3 has also been implicated in the development of resistance to several drugs used against cancers driven by ErbB1 or ErbB2. One of the main challenges in ErbB-targeting therapy is to inactivate signaling mediated by ErbB2-ErbB3 oncogenic receptor complexes. We analyzed the regulatory role of flotillins on ErbB3 levels and ErbB2-ErbB3 complexes in SKBR3, MCF7 and MDA-MB-134-VI human breast cancer cells. Recently, we described a mechanism for interfering with ErbB2 signaling in breast cancer and demonstrated a molecular complex of flotillin scaffolding proteins with ErbB2 and Hsp90. In the present study, flotillins were found to be in a molecular complex with ErbB3, even in cells without the presence of ErbB2 or other ErbB receptors. Depletion of either flotillin-1 or flotillin-2 resulted in downregulation of ErbB3 and a selective reduction of ErbB2-ErbB3 receptor complexes. Moreover, flotillin-2 depletion resulted in reduced activation of Akt and MAPK signaling cascades, and as a functional consequence of flotillin depletion, breast cancer cells showed an impaired cell migration. Altogether, we provide data demonstrating a novel and functional role of flotillins in the regulation of ErbB protein levels and stabilization of ErbB2-ErbB3 receptor complexes. Thus, flotillins are crucial regulators for oncogenic ErbB function and potential targets for cancer treatment.
Insights
Flotillins regulate ErbB3 protein levels and ErbB2-ErbB3 complexes, impacting cancer cell signaling and migration. Targeting flotillins may offer new therapeutic strategies for breast cancer treatment.
Area of Science:
- Molecular biology
- Cell biology
- Cancer research
Background:
- ErbB3 receptor overexpression is common in breast cancer, contributing to carcinogenesis and drug resistance.
- ErbB2-ErbB3 complexes are key oncogenic drivers, posing a challenge for targeted therapies.
- Flotillins are scaffolding proteins previously linked to ErbB2 signaling.
Purpose of the Study:
- To investigate the regulatory role of flotillins in ErbB3 levels and ErbB2-ErbB3 complex formation.
- To determine the functional consequences of flotillin modulation on breast cancer cell behavior.
Main Methods:
- Analysis of flotillin-ErbB3 interactions in human breast cancer cell lines (SKBR3, MCF7, MDA-MB-134-VI).
- Depletion of flotillin-1 or flotillin-2 using knockdown techniques.
- Assessment of ErbB3 levels, ErbB2-ErbB3 complex formation, Akt and MAPK signaling activation, and cell migration.
Main Results:
- Flotillins form molecular complexes with ErbB3, independent of ErbB2.
- Flotillin depletion downregulates ErbB3 and reduces ErbB2-ErbB3 complexes.
- Flotillin-2 depletion impairs Akt and MAPK signaling, leading to reduced breast cancer cell migration.
Conclusions:
- Flotillins play a novel, functional role in regulating ErbB protein levels and stabilizing oncogenic ErbB2-ErbB3 complexes.
- Flotillins are critical for oncogenic ErbB function and represent potential therapeutic targets in cancer treatment.
