Tamoxifen-induced activation of p21Waf1/Cip1 gene transcription is mediated by Early Growth Response-1 protein through the JNK and p38 MAP kinase/Elk-1 cascades in MDA-MB-361 breast carcinoma cells

Kim, Chang Gun; Choi, Byeong Hyeok; Son, Sang Wook; Yi, Seong Joon; Shin, Soon Young; Lee, Young Han

doi:10.1016/j.cellsig.2007.01.008

Cited by 32 publications

(31 citation statements)

References 57 publications

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“…From this shortlist, the potential interaction between Mapk8 (Jnk1) and the transcription factor Elk3 (ETS domain-containing protein 3) was of interest, given reports that activated JNK phosphorylates the ETS family member ELK1 (25,26). Furthermore, the observation that independent shRNAs targeting Mapk8 were enriched in tumors isolated from AC-treated, compared with vehicle-treated, mice implicated a contribution of JNK signaling to tumor cell chemotherapeutic killing in vivo.…”

Section: Resultsmentioning

confidence: 99%

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

Ashenden

Weverwijk

Murugaesu

et al. 2017

Molecular Cancer Therapeutics

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Chemotherapy remains the mainstay of treatment for advanced breast cancer; however, resistance is an inevitable event for the majority of patients with metastatic disease. Moreover, there is little information available to guide stratification of firstline chemotherapy, crucial given the common development of multidrug resistance. Here, we describe an in vivo screen to interrogate the response to anthracycline-based chemotherapy in a syngeneic metastatic breast cancer model and identify JNK signaling as a key modulator of chemotherapy response. Combining in vitro and in vivo functional analyses, we demonstrate that JNK inhibition both promotes tumor cell cytostasis and blocks activation of the proapoptotic protein Bax, thereby antagonizing chemotherapy-mediated cytotoxicity. To investigate the clinical relevance of this dual role of JNK signaling, we developed a proliferation-independent JNK activity signature and demonstrate high JNK activity to be enriched in triple-negative and basal-like breast cancer subtypes. Consistent with the dual role of JNK signaling in vitro, high-level JNK pathway activation in triplenegative breast cancers is associated both with poor patient outcome in the absence of chemotherapy treatment and, in neoadjuvant clinical studies, is predictive of enhanced chemotherapy response. These data highlight the potential of monitoring JNK activity as early biomarker of response to chemotherapy and emphasize the importance of rational treatment regimes, particularly when combining cytostatic and chemotherapeutic agents.

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Section: Resultsmentioning

confidence: 99%

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

Ashenden

Weverwijk

Murugaesu

et al. 2017

Molecular Cancer Therapeutics

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“…In addition, the region between À58 and À51 bp from the p21 transcription initiation site contains consensus early growth response-1 (Egr-1) binding sequences (EBS), which play a major role in regulating p21 transcription in response to resveratrol treatment in K562 cells (13) and to tamoxifen in MDA-MB-361 breast cancer cells (14).…”

Section: Introductionmentioning

confidence: 99%

“…Egr-1 regulates expression of genes involved in the control of growth and apoptosis by transactivating p21, p53, PTEN, transforming growth factor h1, fibronectin, and Gadd45 (13)(14)(15)(16)(17). Significantly reduced Egr-1 expression has been observed during tumor formation in various mammalian cells and tissues (18).…”

Section: Introductionmentioning

confidence: 99%

p21Waf1/Cip1 Expression by Curcumin in U-87MG Human Glioma Cells: Role of Early Growth Response-1 Expression

et al. 2008

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Curcumin, a natural compound, is a well-known chemopreventive agent with potent anticarcinogenic activity in a wide variety of tumor cells. Curcumin inhibits cancer cell proliferation in part by suppressing cyclin D1 and inducing expression of the cyclin-dependent kinase inhibitor p21Waf1/Cip1 . Both p53-dependent and p53-independent mechanisms regulate p21Waf1/Cip1 expression, but the mechanism by which curcumin regulates p21Waf1/Cip1 expression remains unknown. Here, we report that transcription of the p21Waf1/Cip1 gene is activated by early growth response-1 (Egr-1) independently of p53 in response to curcumin treatment in U-87MG human glioblastoma cells. Egr-1 is a transcription factor that helps regulate differentiation, growth, and apoptosis in many cell types. Egr-1 expression is induced by curcumin through extracellular signal-regulated kinase (ERK) and c-Jun NH 2 -terminal kinase (JNK), but not the p38, mitogen-activated protein kinase (MAPK) pathways, which mediate the transactivation of Elk-1. Transient expression of Egr-1 enhanced curcumin-induced p21 Waf1/Cip1 promoter activity, whereas suppression of Egr-1 expression by small interfering RNA abrogated the ability of curcumin to induce p21 Waf1/Cip1 promoter activity. In addition, stable knockdown of Egr-1 expression in U-87MG cells suppressed curcumin-induced p21 expression. Our results indicate that ERK and JNK MAPK/Elk-1/Egr-1 signal cascade is required for p53-independent transcriptional activation of p21 Waf1/Cip1 in response to curcumin in U-87MG human glioblastoma cells. [Cancer Res 2008;68(5):1369-77]

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“…Wenzel et al (40) reported that EGR1 expression in MCF-7 cells was associated with an inhibitory protein for type 1 Ser/Thr protein phosphatase, and that the expression of this protein is reduced in breast cancer cells, breast tumors, and metastases. Chemotherapeutic agent-induced EGR1 expression in breast carcinoma cells led to a p53-independent apoptosis (41). However, the mechanisms underlying the loss of EGR1 expression for the dysregulation of normal breast cell growth are not yet fully understood.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of the human CTP:phosphoethanolamine cytidylyltransferase gene by early growth response protein 1

Zhu

Johnson

Bakovic

2008

Journal of Lipid Research

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Change in phosphoethanolamine pool size in tumor tissues is an important indicator of tumor prognosis and drug therapy efficacy. Phosphoethanolamine is the substrate of the regulatory enzyme CTP:phosphoethanolamine cytidylyltransferase (ECT) in the de novo biosynthesis of phosphatidylethanolamine (PE). Metabolic labeling with [14 C]ethanolamine revealed a reduced ECT activity in MCF-7 breast cancer cells, which led to an accumulation of phosphoethanolamine and a decrease in PE synthesis in comparison with MCF-10A mammary epithelial cells. The enhanced ECT activity in MCF-10A cells was due to significantly elevated CTP:phosphoethanolamine cytidylyltransferase gene (PCYT2) expression, at the level of promoter activity, mRNA, and protein content. The early growth response protein 1 (EGR1) could account for most of the elevated ECT activity in MCF-10A cells relative to MCF-7 cells, as evidenced by promoter-luciferase reporter assays, gelshift analyses, and by alterations in the EGR1 gene expression. In MCF-7 cells, EGR1 is present at lower levels and the basal PCYT2 promoter activity is maintained by proximal CAAT and GC regions and by elevated nuclear NFkB activity. Together, these data demonstrate that EGR1 is an important transcriptional stimulator of the human PCYT2 and that conditions that modify EGR1 also affect the function of ECT and consequently PE synthesis.-Zhu, L., C. Johnson, and M. Bakovic. Stimulation of the human CTP: phosphoethanolamine cytidylyltransferase gene by early growth response protein 1.

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Tamoxifen-induced activation of p21Waf1/Cip1 gene transcription is mediated by Early Growth Response-1 protein through the JNK and p38 MAP kinase/Elk-1 cascades in MDA-MB-361 breast carcinoma cells

Cited by 32 publications

References 57 publications

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

p21Waf1/Cip1 Expression by Curcumin in U-87MG Human Glioma Cells: Role of Early Growth Response-1 Expression

Stimulation of the human CTP:phosphoethanolamine cytidylyltransferase gene by early growth response protein 1

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