Early-Stage Metastasis Requires Mdm2 and Not p53 Gain of Function

Hauck, Paula M.; Wolf, Eric R.; Olivos, David J.; Batuello, Christopher N.; McElyea, Kyle; McAtarsney, Ciaran P.; Cournoyer, R. Michael; Sandusky, George E.; Mayo, Lindsey D.

doi:10.1158/1541-7786.mcr-17-0174

Cited by 20 publications

(28 citation statements)

References 49 publications

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“…We tested the role of MDM2 or MDMX knockdown in the metastatic TNBC MDA-MB-231 cells by assessing the tumor volumes and the number of endpoint CTCs. We found that MDM2 knockdown in MDA-MB-231 orthotopic tumors drastically increased MDMX protein levels and, in support of previously published data [5], also suppressed the number of CTCs. Importantly, we report, for the first time to our knowledge, that MDMX was indispensable in the metastasis cascade, because knocking down MDMX significantly blocked the presence of CTCs.…”

Section: Introductionsupporting

confidence: 92%

“…MDM2 promotes early-stage metastasis and CTCs in TNBC [5], but the role of MDMX has not been defined. To better understand the role of MDM2 and MDMX in breast cancer metastasis, we compared the biological outcomes of knocking them down in the highly metastatic triple-negative claudin-low MDA-MB-231 cells.…”

Section: Resultsmentioning

confidence: 99%

“…The involvement of MDM2 in promoting breast cancer through p53-independent pathways is becoming increasingly clear. A mouse model study showed that MDM2 promotes early-stage metastasis in TNBCs, providing the first in vivo evidence for a role of MDM2 in promoting circulating tumor cells (CTCs) [5]. However, ERα + breast cancer models often are not metastatic, and we and others have shown that estrogen signaling increases their cell proliferation in vitro through a p53-independent MDM2 pathway [6, 7].…”

Section: Introductionmentioning

confidence: 99%

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Context-dependent roles of MDMX (MDM4) and MDM2 in breast cancer proliferation and circulating tumor cells

et al. 2019

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IntroductionMany human breast cancers overexpress the E3 ubiquitin ligase MDM2 and its homolog MDMX. Expression of MDM2 and MDMX occurs in estrogen receptor α-positive (ERα+) breast cancer and triple-negative breast cancer (TNBC). There are p53-independent influences of MDM2 and MDMX, and 80% of TNBC express mutant p53 (mtp53). MDM2 drives TNBC circulating tumor cells (CTCs) in mice, but the context-dependent influences of MDM2 and MDMX on different subtypes of breast cancers expressing mtp53 have not been determined.MethodsTo assess the context-dependent roles, we carried out MDM2 and MDMX knockdown in orthotopic tumors of TNBC MDA-MB-231 cells expressing mtp53 R280K and MDM2 knockdown in ERα+ T47D cells expressing mtp53 L194F. The corresponding cell proliferation was scored in vitro by growth curves and in vivo by orthotopic tumor volumes. Cell migration was assessed in vitro by wound-healing assays and cell intravasation in vivo by sorting GFP-positive CTCs by flow cytometry. The metastasis gene targets were determined by an RT-PCR array card screen and verified by qRT-PCR and Western blot analysis.ResultsKnocking down MDMX or MDM2 in MDA-MB-231 cells reduced cell migration and CTC detection, but only MDMX knockdown reduced tumor volumes at early time points. This is the first report of MDMX overexpression in TNBC enhancing the CTC phenotype with correlated upregulation of CXCR4. Experiments were carried out to compare MDM2-knockdown outcomes in nonmetastatic ERα+ T47D cells. The knockdown of MDM2 in ERα+ T47D orthotopic tumors decreased primary tumor volumes, supporting our previous finding that estrogen-activated MDM2 increases cell proliferation.ConclusionsThis is the first report showing that the expression of MDM2 in ERα+ breast cancer and TNBC can result in different tumor-promoting outcomes. Both MDMX and MDM2 overexpression in TNBC MDA-MB-231 cells enhanced the CTC phenotype. These data indicate that both MDM2 and MDMX can promote TNBC metastasis and that it is important to consider the context-dependent roles of MDM2 family members in different subtypes of breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1094-8) contains supplementary material, which is available to authorized users.

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Section: Introductionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Context-dependent roles of MDMX (MDM4) and MDM2 in breast cancer proliferation and circulating tumor cells

et al. 2019

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“…Pictures were acquired every hour for a period of 48 hours. Pictures were analysed with ImageJ and migration area was calculated with MRI Wound Healing Tool ( http://dev.mri.cnrs.fr/projects/imagej-macros/wiki/Wound_Healing_Tool ) as previously published [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

Nrf2 protects stellate cells from Smad-dependent cell activation

Prestigiacomo

Suter‐Dick

2018

PLoS ONE

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Hepatic stellate cells (HSC) orchestrate the deposition of extracellular matrix (ECM) and are the primary effector of liver fibrosis. Several factors, including TGF-β1, PDGF and oxidative stress, have been shown to trigger HSC activation. However, the involvement of cellular defence mechanisms, such as the activation of antioxidant response by Nrf2/Keap1 in the modulation of HSC activation is not known. The aim of this work was to elucidate the role of Nrf2 pathway in HSC trans-differentiation involved in the development of fibrosis. To this end, we repressed Nrf2 and Keap1 expression in HSC with specific siRNAs. We then assessed activation markers, as well as proliferation and migration, in both primary and immortalised human HSCs exposed to Smad inhibitors (SB-431542 hydrate and SB-525334), TGF-β1 and/or PDGF. Our results indicate that knocking down Nrf2 induces HSC activation, as shown by an increase in αSMA-positive cells and by gene expression induction of ECM components (collagens and fibronectin). HSC with reduced Nrf2-levels also showed an increase in migration and a decrease in proliferation. We could also demonstrate that the activation of Nrf2-deficient HSC involves the TGF-β1/Smad pathway, as the activation was successfully inhibited with the two tested Smad inhibitors. Moreover, TGF-β1 elicited a stronger induction of HSC activation markers in Nrf2 deficient cells than in wild type cells. Thus, our data suggest that Nrf2 limits HSCs activation, through the inhibition of the TGF-β1/Smad pathway in HSCs.

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“…Indeed, the inhibition of the interaction between p53-Mdm2 has been deeply investigated and it is considered an interesting strategy for cancer therapy. Mdm2 is considered a potent tumor promoter in numerous cancers and it has been highly associated with metastasis [ 148 , 149 ]. It was also described that Mdm2 ubiquitinates insulin-like growth factor type 1 receptor (IGF-1R), inducing its further degradation, thus affecting cell growth in a p53 independent-manner [ 150 ].…”

Section: Emt Regulation By E3 Ubiquitin-ligasesmentioning

confidence: 99%

Regulation of Epithelial–Mesenchymal Plasticity by the E3 Ubiquitin-Ligases in Cancer

Rodríguez-Alonso

Casas-Pais

Roca-Lema

et al. 2020

Cancers

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The epithelial–mesenchymal plasticity (EMP) is a process by which epithelial cells acquire the ability to dynamically switch between epithelial and mesenchymal phenotypic cellular states. Epithelial cell plasticity in the context of an epithelial-to-mesenchymal transition (EMT) confers increased cell motility, invasiveness and the ability to disseminate to distant sites and form metastasis. The modulation of molecularly defined targets involved in this process has become an attractive therapeutic strategy against cancer. Protein degradation carried out by ubiquitination has gained attention as it can selectively degrade proteins of interest. In the ubiquitination reaction, the E3 ubiquitin-ligases are responsible for the specific binding of ubiquitin to a small subset of target proteins, and are considered promising anticancer drug targets. In this review, we summarize the role of the E3 ubiquitin-ligases that control targeted protein degradation in cancer-EMT, and we highlight the potential use of the E3 ubiquitin-ligases as drug targets for the development of small-molecule drugs against cancer.

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Early-Stage Metastasis Requires Mdm2 and Not p53 Gain of Function

Cited by 20 publications

References 49 publications

Context-dependent roles of MDMX (MDM4) and MDM2 in breast cancer proliferation and circulating tumor cells

Context-dependent roles of MDMX (MDM4) and MDM2 in breast cancer proliferation and circulating tumor cells

Nrf2 protects stellate cells from Smad-dependent cell activation

Regulation of Epithelial–Mesenchymal Plasticity by the E3 Ubiquitin-Ligases in Cancer

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