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Lack of interaction between ErbB2 and insulin receptor substrate signaling in breast cancer
Susan M Farabaugh1, Bonita T Chan2, Xiaojiang Cui2
1Women's Cancer Research Center, Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Magee Women's Research Institute, 204 Craft Avenue, Room A412, Pittsburgh, PA, 15213, USA.
Background:
ErbB2 Receptor Tyrosine Kinase 2 (ErbB2, HER2/Neu) is amplified in breast cancer and associated with poor prognosis. Growing evidence suggests interplay between ErbB2 and insulin-like growth factor (IGF) signaling. For example, ErbB2 inhibitors can block IGF-induced signaling while, conversely, IGF1R inhibitors can inhibit ErbB2 action. ErbB receptors can bind and phosphorylate insulin receptor substrates (IRS) and this may be critical for ErbB-mediated anti-estrogen resistance in breast cancer. Herein, we examined crosstalk between ErbB2 and IRSs using cancer cell lines and transgenic mouse models.
Methods:
MMTV-ErbB2 and MMTV-IRS2 transgenic mice were crossed to create hemizygous MMTV-ErbB2/MMTV-IRS2 bigenic mice. Signaling crosstalk between ErbB2 and IRSs was examined in vitro by knockdown or overexpression followed by western blot analysis for downstream signaling intermediates and growth assays.
Results:
A cross between MMTV-ErbB2 and MMTV-IRS2 mice demonstrated no enhancement of ErbB2 mediated mammary tumorigenesis or metastasis by elevated IRS2. Substantiating this, overexpression or knockdown of IRS1 or IRS2 in MMTV-ErbB2 mammary cancer cell lines had little effect upon ErbB2 signaling. Similar results were obtained in human mammary epithelial cells (MCF10A) and breast cancer cell lines.
Conclusion:
Despite previous evidence suggesting that ErbB receptors can bind and activate IRSs, our findings indicate that ErbB2 does not cooperate with the IRS pathway in these models to promote mammary tumorigenesis.
Insights
ErbB2 (HER2/Neu) amplification in breast cancer does not cooperate with the insulin receptor substrate (IRS) pathway to promote tumor growth or metastasis, despite prior evidence of signaling interplay. This study found no enhancement of ErbB2-driven mammary tumorigenesis by elevated IRS2.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- ErbB2 (HER2/Neu) amplification in breast cancer correlates with poor prognosis.
- Evidence suggests interplay between ErbB2 and insulin-like growth factor (IGF) signaling pathways.
- ErbB receptors may bind and phosphorylate insulin receptor substrates (IRS), potentially mediating anti-estrogen resistance.
Purpose of the Study:
- To investigate the crosstalk between ErbB2 and insulin receptor substrates (IRSs).
- To determine if ErbB2 cooperates with the IRS pathway in mammary tumorigenesis.
- To examine the role of IRS1 and IRS2 in ErbB2-mediated signaling.
Main Methods:
- Utilized MMTV-ErbB2 and MMTV-IRS2 transgenic mouse models, creating bigenic mice.
- Examined signaling crosstalk in vitro via knockdown/overexpression of IRS1/IRS2.
- Performed western blot analysis for downstream signaling and growth assays in cell lines.
Main Results:
- Hemizygous MMTV-ErbB2/MMTV-IRS2 bigenic mice showed no enhanced ErbB2-mediated mammary tumorigenesis or metastasis.
- Overexpression or knockdown of IRS1 or IRS2 had minimal impact on ErbB2 signaling in MMTV-ErbB2 cell lines.
- Similar findings were observed in human mammary epithelial and breast cancer cell lines.
Conclusions:
- ErbB2 does not cooperate with the IRS pathway to promote mammary tumorigenesis in the studied models.
- Contrary to previous suggestions, ErbB2 activation of IRSs may not be critical for ErbB2-driven cancer progression.
- The findings challenge the presumed role of ErbB2-IRS pathway interaction in breast cancer development.
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