Abstract
The coexpression of erbB3 and erbB2 is frequently observed in breast cancer; and erbB3 has a critical role in erbB2 promotion of breast cancer progression and anti-estrogen resistance. In this study, we determine the role of erbB3 in erbB2-mediated paclitaxel resistance in breast cancer cells. The overexpression of exogenous erbB3 via either stable or transient transfection in erbB2-overexpressing, but not epidermal growth factor receptor (EGFR)-expressing, breast cancer cells significantly decreases paclitaxel-induced growth inhibition and apoptosis. Consistently, knockdown of erbB3 expression with a specific short hairpin RNA (shRNA) in breast cancer cells with coexpression of both erbB2 and erbB3 enhances paclitaxel-induced apoptosis evidenced by increased DNA fragmentation, poly (ADP-ribose) polymerase (PARP) cleavage and activation of caspase-3 and -8. Furthermore, while forced overexpression of erbB3 increases, specific knockdown of erbB3 decreases the expression levels of Survivin only in the erbB2-overexpressing breast cancer cells. Targeting Survivin with specific shRNA overcomes paclitaxel resistance without effect on the expression levels of either erbB2 or erbB3. Mechanistic studies indicate that the specific phosphoinositide 3-kinase (PI-3K), Akt and mammalian target of rapamycin (mTOR) inhibitors, but not the mitogen-activated protein kinase kinase (MEK) inhibitor, not only abrogate erbB3-mediated upregulation of Survivin, but also reinforce the erbB2/erbB3-coexpressing breast cancer cells to paclitaxel-induced growth inhibition. These data demonstrate that heterodimerization of erbB2/erbB3 is a prerequisite for erbB2 tyrosine kinase activation; and elevated expression of erbB3 is required for erbB2-mediated paclitaxel resistance in breast cancer cells via PI-3K/Akt/mTOR signaling pathway-dependent upregulation of Survivin. Our studies suggest that new strategies targeting erbB3 or Survivin may enhance the efficacy of chemotherapeutic agents against erbB2-overexpressing breast cancer.
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Abbreviations
- ER:
-
estrogen receptor
- EGFR:
-
epidermal growth factor receptor
- MAPK:
-
mitogen-activated protein kinase
- MEK:
-
MAPK kinase
- PI-3K:
-
phosphoinositide 3-kinase
- mAb:
-
monoclonal antibody
- mTOR:
-
mammalian target of rapamycin
- PARP:
-
poly(ADP-ribose) polymerase
- TUBB3:
-
class III β-tubulin
- CXCR4:
-
C-X-C chemokine receptor type 4
- MRP1:
-
multi-drug resistance protein 1
- TXR1:
-
taxol-resistance gene 1
- NSCLC:
-
non-small cell lung cancer
- shRNA:
-
short-hairpin RNA
- ELISA:
-
enzyme-linked immunosorbent assay
- PAGE:
-
polyacrylamide gel electrophoresis
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Acknowledgements
We thank Dr Haihua Gu for providing the pLKO.1-ErbB3shRNA expression vector and lentivirus packaging plasmids pCMV-VSVG and pCMV-ΔA.9. We also thank Ms Lisa Litzenberger for her excellent art preparation. This work was supported in part by a research Grant from Susan G Komen for the Cure (to BL).
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Wang, S., Huang, X., Lee, CK. et al. Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin. Oncogene 29, 4225–4236 (2010). https://doi.org/10.1038/onc.2010.180
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DOI: https://doi.org/10.1038/onc.2010.180
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