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Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin

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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Correspondence to B Liu.

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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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