CIP2A is a target of bortezomib in human triple negative breast cancer cells

Abstract

IntroductionTriple negative breast cancer (TNBC) is very aggressive and currently has no specific therapeutic targets, such as hormone receptors or human epidermal growth factor receptor type 2 (HER2); therefore, prognosis is poor. Bortezomib, a proteasome inhibitor, may exert efficacy in TNBC through its multiple cellular effects. Here, we tested the efficacy of bortezomib and examined the drug mechanism in breast cancer cells.MethodsFive breast cancer cell lines: TNBC HCC-1937, MDA-MB-231, and MDA-MB-468; HER2-overexpressing MDA-MB-453; and estrogen receptor positive MCF-7 were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western Blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interfering RNA (siRNA). In vivo efficacy of bortezomib was tested in nude mice with breast cancer xenografts. Immunohistochemical study was performed on tumor tissues from patients with TNBC.ResultsBortezomib induced significant apoptosis, which was independent of its proteasome inhibition, in the three TNBC cell lines, but not in MDA-MB-453 or MCF-7 cells. Furthermore, cancerous inhibitor of protein phosphatase 2A (CIP2A), a cellular inhibitor of protein phosphatase 2A (PP2A), mediated the apoptotic effect of bortezomib. We showed that bortezomib inhibited CIP2A in association with p-Akt downregulation in a dose- and time-dependent manner in all sensitive TNBC cells, whereas no alterations in CIP2A expression and p-Akt were noted in bortezomib-resistant cells. Overexpression of CIP2A upregulated p-Akt and protected MDA-MB-231 and MDA-MB-468 cells from bortezomib-induced apoptosis, whereas silencing CIP2A by siRNA overcame the resistance to bortezomib-induced apoptosis in MCF-7 cells. In addition, bortezomib downregulated CIP2A mRNA but did not affect the degradation of CIP2A protein. Furthermore, bortezomib exerted in vivo antitumor activity in HCC-1937 xenografted tumors, but not in MCF-7 tumors. Bortezomib downregulated CIP2A expression in the HCC-1937 tumors but not in the MCF-7 tumors. Importantly, CIP2A expression is readily detectable in tumor samples from TNBC patients.ConclusionsCIP2A is a major determinant mediating bortezomib-induced apoptosis in TNBC cells. CIP2A may thus be a potential therapeutic target in TNBC.

Increased serum tumor necrosis factor receptor-associated factor-6 expression in patients with non-metastatic triple-negative breast cancer

“…For example, in a study investigating multiple myeloma, bortezomib treatment was observed to downregulate TRAF6 expression at the protein and mRNA levels, resulting in a reduction in osteoclast formation (40). Similarly, Tseng et al (41) investigated the efficacy of bortezomib treatment in vitro and identified that TNBC cells were sensitive to its cytotoxic activity. The aforementioned data supports the results of the current study; therefore, it is proposed that elevated TRAF6 may be a novel therapeutic target for patients with TNBC.…”

Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy

“…TNBC are characterized by occurrence in younger women, aggressive behaviors with a metastasis potential, high recurrence rate and poor prognosis (11). Because of a lack of targeted therapies (such as anti-HER2 therapy or hormone therapy), chemotherapy is currently the primary treatment of TNBC.…”

“…In 2009, Côme et al (10) demonstrated that CIP2A is associated with clinical aggressivity in human breast cancer and promotes the malignant growth of breast cancer cells (10). Then in 2012, Tseng et al (11) found that CIP2A is a target of the proteasome inhibitor bortezomib in human TNSC cells. However, the expression and the role that CIP2A serves in pathogenesis of human TNBC requires further investigation.…”

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

“…Moreover, our study also indicates that this induction of chemokine and cytokine levels is significantly sensitive to NF-kB inhibitor treatment, although there is marginal effect after lapatinib treatment. (47,48) Activation of NF-kB signal follows both canonical and non-canonical pathways, and crosstalk between these two pathways appears to exist. (49) Our experiments indicated that the level of IkB is unaltered in both cell lines and the phosphorylation of IkB in resistant cells is sensitive to NFkB inhibitor treatment.…”