Cyclin E overexpression enhances cytokine-mediated apoptosis in MCF7 breast cancer cells

Dhillon, Navdeep; Mudryj, Maria

doi:10.1038/sj.gene.6363973

Cited by 11 publications

(8 citation statements)

References 38 publications

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“…An increased level in Cyclin E, which is implicated in the G 1 /S transition, also accords well with this deregulated mitotic progression. Consistently, Cyclin E up-regulation was also associated with cell death (29).…”

Section: Discussionsupporting

confidence: 60%

Aurora B Is Regulated by the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase (MAPK/ERK) Signaling Pathway and Is a Valuable Potential Target in Melanoma Cells

Bonet

Giuliano

Ohanna

et al. 2012

Journal of Biological Chemistry

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Background: BRAFV600E melanoma cells develop resistance to vemurafenib. The BRAF/ERK axis controls melanoma cell proliferation. Aurora B is a key actor of mitosis. Results: The BRAF/ERK axis regulates Aurora B. Vemurafenib-resistant melanoma cells are sensitive to Aurora B inhibition. Conclusion: Aurora B is a valuable target in melanoma cells. Significance: Our findings provide insights into Aurora B regulation and on new druggable targets to overcome vemurafenib resistance.

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Section: Discussionsupporting

confidence: 60%

Aurora B Is Regulated by the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase (MAPK/ERK) Signaling Pathway and Is a Valuable Potential Target in Melanoma Cells

Bonet

Giuliano

Ohanna

et al. 2012

Journal of Biological Chemistry

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“…The levels of cyclin E amplification and overexpression in breast tumors are lower than those described for HER2 (breast cancer) or MET (lung cancer) genes. The most likely explanation is that excessive levels of cyclin E would lead to cell death or senescence (32,33).…”

Section: Resultsmentioning

confidence: 99%

Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2 ⁺ breast cancer patients

Scaltriti

Eichhorn

Cortés³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

296

207

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Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant HER2 amplified breast cancer cells by chronic exposure to trastuzumab treatment. Genomewide copy-number variation analyses of the resistant cells compared with parental cells revealed a focal amplification of genomic DNA containing the cyclin E gene. In a cohort of 34 HER2 + patients treated with trastuzumab-based therapy, we found that cyclin E amplification/overexpression was associated with a worse clinical benefit (33.3% compared with 87.5%, P < 0.02) and a lower progression-free survival (6 mo vs. 14 mo, P < 0.002) compared with nonoverexpressing cyclin E tumors. To dissect the potential role of cyclin E in trastuzumab resistance, we studied the effects of cyclin E overexpression and cyclin E suppression. Cyclin E overexpression resulted in resistance to trastuzumab both in vitro and in vivo. Inhibition of cyclin E activity in cyclin E-amplified trastuzumab resistant clones, either by knockdown of cyclin E expression or treatment with cyclin-dependent kinase 2 (CDK2) inhibitors, led to a dramatic decrease in proliferation and enhanced apoptosis. In vivo, CDK2 inhibition significantly reduced tumor growth of trastuzumab-resistant xenografts. Our findings point to a causative role for cyclin E overexpression and the consequent increase in CDK2 activity in trastuzumab resistance and suggest that treatment with CDK2 inhibitors may be a valid strategy in patients with breast tumors with HER2 and cyclin E coamplification/overexpression. HER2 is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, which includes EGFR itself, HER2, HER3, and HER4. Homo-or heterodimerization of these receptors results in phosphorylation of residues in the intracellular domain and consequent recruitment of adapter molecules responsible for the initiation of several signaling pathways involved in cell proliferation and survival (1, 2). Approximately 20% of breast cancers exhibit HER2 gene amplification/overexpression, resulting in an aggressive tumor phenotype and reduced survival (3, 4). Therapy of HER2 + breast cancer with anti-HER2 agents, including monoclonal antibodies and small molecule tyrosine kinase inhibitors, has markedly improved the outcome of this disease (5). Trastuzumab, a recombinant humanized monoclonal antibody that binds to the extracellular domain of HER2, improves survival in patients with HER2 + breast cancer, in both the metastatic (6, 7) and adjuvant settings (8). The overall antitumor activity of trastuzumab is due to a combination of mechanisms, including inhibition of ligandindependent HER2 dimerization (9), HER2 down-regulation (10,11), that lead to disruption of HER2-dependent PI3K/Akt signaling (12) and induction of G1 arrest through stabilization of the CDK inhibitor p27 (13). In addition, trastuzumab also mediates antibod...

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“…Because cytoplasmic localization of PELP1 leads to upregulation of cyclin E, it is possible that the hypersensitivity of the cytoplasmic PELP1 -expressing cells may result from the noted up-regulation of cyclin E protein as shown before (21) or an increased proliferation or both. However, because we did not observe any change in the levels of cyclin E mRNA, it seems that the observed increased cyclin E protein may not be a consequence of the putative effects of PELP1 on the cell cycle and that cytoplasmic PELP1 may directly or indirectly influence the levels of cyclin E via a posttranscription mechanism, which is yet-to-be identified.…”

Section: Discussionmentioning

confidence: 99%

Altered localization of a coactivator sensitizes breast cancer cells to tumor necrosis factor–induced apoptosis

Rayala

Mascarenhas

Vadlamudi

et al. 2006

Molecular Cancer Therapeutics

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Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) is a novel coregulator of the estrogen receptor that plays a role in both genomic and nongenomic actions of the estrogen receptor. Emerging studies suggest that in addition to the nuclear localization of PELP1, it is predominantly localized in the cytoplasm in human breast tumors, leading to excessive nongenomic signaling and possibly to tamoxifen resistance. The mechanisms underlying resistance to hormones in preclinical model systems remain under intense investigation. In an effort to develop a model system to treat tumor cells with cytoplasmic PELP1 expression and tamoxifen resistance, here we used the cytokine tumor necrosis factor (TNF)-A. We found that clones of MCF-7 human breast cancer cells overexpressing PELP1 in the cytoplasm were distinctly sensitive to TNF-A-induced apoptosis than were wild-type nuclear PELP1 -and pcDNA vector -expressing clones as revealed by cell growth assay, cell cycle analysis, Annexin V staining, and terminal deoxynucleotidyl transferasemediated dUTP nick end labeling assay. We also found that the clones with cytoplasmic PELP1 overexpression had significantly less antiapoptotic protein Bcl-2 and nuclear factor-KB DNA binding, but increased cyclin E expression, further supporting evidence that these cells are sensitive to apoptosis. The mechanism behind TNFinduced apoptosis in these cells involves caspases, as revealed by poly(ADP-ribose) polymerase cleavage and the broad-spectrum caspase inhibitor Z-VAD-inhibited apoptosis. In conclusion, our results suggest that altered localization of PELP1 promotes heightened sensitivity to TNF-A in MCF-7 cells, paving the way for developing new treatment strategies for tumors with cytoplasmic PELP1 expression. [Mol Cancer Ther 2006;5(2):230 -7]

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Cyclin E overexpression enhances cytokine-mediated apoptosis in MCF7 breast cancer cells

Cited by 11 publications

References 38 publications

Aurora B Is Regulated by the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase (MAPK/ERK) Signaling Pathway and Is a Valuable Potential Target in Melanoma Cells

Aurora B Is Regulated by the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase (MAPK/ERK) Signaling Pathway and Is a Valuable Potential Target in Melanoma Cells

Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2 ⁺ breast cancer patients

Altered localization of a coactivator sensitizes breast cancer cells to tumor necrosis factor–induced apoptosis

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Cyclin E overexpression enhances cytokine-mediated apoptosis in MCF7 breast cancer cells

Cited by 11 publications

References 38 publications

Aurora B Is Regulated by the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase (MAPK/ERK) Signaling Pathway and Is a Valuable Potential Target in Melanoma Cells

Aurora B Is Regulated by the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase (MAPK/ERK) Signaling Pathway and Is a Valuable Potential Target in Melanoma Cells

Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2 + breast cancer patients

Altered localization of a coactivator sensitizes breast cancer cells to tumor necrosis factor–induced apoptosis

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Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2 ⁺ breast cancer patients