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.

Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3

“…Unlike ErbB1 and ErbB2, ErbB3 does not require adaptor proteins to interact with the regulatory p85 subunit of PI3K, instead interacting directly through up to 6 potential phosphotyrosines. Consequently, ErbB3 activation proficiently triggers PI3K signaling and activation of this pathway is frequently observed in tumors that escape from currently marketed ErbB-directed inhibitors (4,6,8,27), as well as hormonal therapy (28,29) and chemotherapy (30,31). Thus, inhibition of ErbB3 activation by heregulin is a worthy therapeutic strategy that is being actively pursued (16,17).…”

miR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer

“…As survivin has been identified as an anti-apoptosis gene in a variety of cancers [24,25], and may partially lead to drug resistance [26,27], we hypothesized that a negative correlation should exist between miR-218 and survivin expression. Indeed, drug-resistant MCF-7/A02 and CALDOX cells, which express low levels of miR-218 (Fig.…”

First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors

“…Recent studies suggest that HER3 pathway activation is important in the development of resistance to EGFR-and HER2-targeted treatments (2)(3)(4)(5)(6). HER3 expression has been described as an adverse prognostic factor in many tumor types including breast, lung, ovarian, and colon cancers (7)(8)(9)(10)(11).…”