High ERK Protein Expression Levels Correlate with Shorter Survival in Triple-Negative Breast Cancer Patients

Bartholomeusz, Chandra; González-Angulo, Ana M.; Liu, Ping; Hayashi, Naoki; Lluch, Aña; Ferrer-Lozano, Jaime; Hortobágyi, Gabriel N.

doi:10.1634/theoncologist.2011-0377

Cited by 112 publications

(82 citation statements)

References 34 publications

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“…The suppression of the MAPK pathway by the MEK inhibitor selumetinib was found to be effective in preventing lung metastasis of TNBC through the reversal of epithelial-mesenchymal transition, as reported in vitro and in vivo [37]. In patients with TNBC, the overexpression of ERK2 was found to indicate a high risk of death [38]. As shown in Fig.…”

Section: Discussionmentioning

confidence: 58%

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

Ono

Sowa

Horinaka

et al. 2018

Breast Cancer Res Treat

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Purpose Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Eribulin was approved for the treatment of metastatic breast cancer through the EMBRACE trial, and a subgroup analysis in this clinical trial indicated the efficacy of eribulin in patients with TNBC. However, the prognosis of patients with TNBC is still poor due to various molecular characteristics. Therefore, there is an urgent need for a more effective treatment for the management of TNBC. Methods We investigated the synergistic effect of a novel histone deacetylase (HDAC) inhibitor, OBP-801, and eribulin in TNBC cell lines because OBP-801 has been known to enhance the anti-tumor activities of other chemotherapeutic agents. The cell growth was analyzed, and the flow cytometry analysis was conducted to evaluate the effects on cell cycle and the induction of apoptosis. The mechanism underlying the enhancement of inhibition of TNBC cell growth was investigated through Western blot analyses. Results The combination treatment of OBP-801 with eribulin showed the synergistic inhibition of the growth in TNBC cells, involved with the enhancement of apoptosis. We, for the first time, found that eribulin upregulated survivin and also that OBP-801 could remarkably suppress the upregulation of survivin by eribulin. Moreover, this combination potently suppressed Bcl-xL and the MAPK pathway compared with either agent alone. Conclusion We found that the combination of OBP-801 and eribulin synergistically inhibited the growth with apoptosis in TNBC cells, suggesting that this combination might be a promising novel strategy for treating TNBC patients.

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Section: Discussionmentioning

confidence: 58%

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

Ono

Sowa

Horinaka

et al. 2018

Breast Cancer Res Treat

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“…In TNBCs, these two pathways are known to be activated and are associated with a poor prognosis (38,39). A recent study suggested that a combination regimen with MEK/ERK and PI3K inhibitors might effectively be used to treat basal-like breast cancers (40).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide Profiling of AP-1–Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer

et al. 2014

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Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties. Cancer Res; 74(14); 3983-94. Ó2014 AACR.

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“…Additionally, studies have reported a trend toward higher MAPK signaling in the primary tumors of nodepositive patients than in the primary tumors of nodenegative patients [11]. It was reported recently that the levels of ERK1/2 expression were correlated with shorter survival in triple-negative breast cancer patients [13]. Studies have also shown that the expression of ERK1/2 was higher in breast cancer specimens, compared with control tissues, and was higher in Stage III patients than in Stage I and Stage II patients [14].…”

Section: Introductionmentioning

confidence: 98%

High nuclear phosphorylated extracellular signal-regulated kinase expression associated with poor differentiation, larger tumor size, and an advanced stage of breast cancer

Kuo¹,

Hsu²,

Chang³

et al. 2013

pjp

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Extracellular signal-regulated kinase (ERK1/2) is implicated in the malignant behavior of breast cancer cells. However, previous clinical-pathological studies have shown that expression of activated/phosphorylated ERK1/2 is not associated with enhanced proliferation and invasion of mammary carcinomas. ERK1/2 is expressed in the cytoplasm, and activated/phosphorylated ERK1/2 translocates to the nucleus. The aim of this study is to evaluate nuclear phosphorylated ERK1/2 as a biomarker for breast cancer prognosis. The clinical-pathological relation of cytoplasmic/nuclear phosphorylated ERK1/2 was analyzed in 105 surgically resected breast cancer specimens by immunohistochemistry with tissue microarray. The results showed that non-neoplastic breast tissue mainly showed faint phosphorylated ERK1/2 staining. No statistically significant association was found between the level of cytoplasmic phosphorylated ERK1/2 expression and the clinical features of the disease. High nuclear phosphorylated ERK1/2 expression was associated with high grade (poor differentiation, p = 0.010), high T status (larger tumor size, p = 0.033), and an advanced stage (p = 0.018) of the disease. Thus, nuclear phosphorylated ERK1/2 is associated with enhanced proliferation and invasion of mammary carcinomas and may be a biomarker for breast cancer prognosis and the determination of therapeutic strategies.

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High ERK Protein Expression Levels Correlate with Shorter Survival in Triple-Negative Breast Cancer Patients

Abstract: ABSTRACT

Cited by 112 publications

References 34 publications

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

Genome-wide Profiling of AP-1–Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer

High nuclear phosphorylated extracellular signal-regulated kinase expression associated with poor differentiation, larger tumor size, and an advanced stage of breast cancer

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