NRG1 regulates Fra-1 transcription and metastasis of triple-negative breast cancer cells via the c-Myc ubiquitination as manipulated by ERK1/2-mediated Fbxw7 phosphorylation

Shu, Le; Chen, Ao; Li, Linrui; Yao, Lun; He, Yangbo; Xu, Jianbo; Gu, Wei; Li, Qiang; Wang, Kun; Zhang, Tongcun; Liu, Guoquan

doi:10.1038/s41388-021-02142-4

Cited by 10 publications

(10 citation statements)

References 31 publications

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“…The sequential epigenetic events involved in FOSL1 transcriptional elongation depend on both upstream and intronic enhancers, controlled by multiple nuclear oncoproteins, such as c-Myc and AP-1. The pathway responsible for the ERK-induced recruitment of c-Myc to the FOSL1 promoter in response to neuregulin (NRG1) has been recently elucidated in breast cancer [11]. Multiple AP-1 binding sites mediate the FOSL1 positive autoregulation, which amplifies the effect of Fra-1 posttranslational accumulation.…”

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confidence: 99%

The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting

Casalino

Talotta²,

Cimmino

et al. 2022

Cancers

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The genetic and epigenetic changes affecting transcription factors, coactivators, and chromatin modifiers are key determinants of the hallmarks of cancer. The acquired dependence on oncogenic transcriptional regulators, representing a major determinant of cancer cell vulnerability, points to transcription factors as ideal therapeutic targets. However, given the unavailability of catalytic activities or binding pockets for small-molecule inhibitors, transcription factors are generally regarded as undruggable proteins. Among components of the AP-1 complex, the FOS-family transcription factor Fra-1, encoded by FOSL1, has emerged as a prominent therapeutic target. Fra-1 is overexpressed in most solid tumors, in response to the BRAF-MAPK, Wnt-beta-catenin, Hippo-YAP, IL-6-Stat3, and other major oncogenic pathways. In vitro functional analyses, validated in onco-mouse models and corroborated by prognostic correlations, show that Fra-1-containing dimers control tumor growth and disease progression. Fra-1 participates in key mechanisms of cancer cell invasion, Epithelial-to-Mesenchymal Transition, and metastatic spreading, by driving the expression of EMT-inducing transcription factors, cytokines, and microRNAs. Here we survey various strategies aimed at inhibiting tumor growth, metastatic dissemination, and drug resistance by interfering with Fra-1 expression, stability, and transcriptional activity. We summarize several tools aimed at the design and tumor-specific delivery of Fra-1/AP-1-specific drugs. Along with RNA-based therapeutics targeting the FOSL1 gene, its mRNA, or cognate regulatory circRNAs, we will examine the exploitation of blocking peptides, small molecule inhibitors, and innovative Fra-1 protein degraders. We also consider the possible caveats concerning Fra-1 inhibition in specific therapeutic contexts. Finally, we discuss a recent suicide gene therapy-based approach, aimed at selectively killing the Fra-1-overexpressing neoplastic cells.

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confidence: 99%

The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting

Casalino

Talotta²,

Cimmino

et al. 2022

Cancers

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“…In triple negative breast cancer (TNBC), NRG1 regulates Fra-1 expression and coordinates cancer cell metastasis via the novel ERK1 / 2-Fbxw7-c-Myc pathway. This makes NGR1 a possible target for the treatment of TNBC (49). In the same way, NRG1 has emerged as a promising target for targeted therapy in non-small cell lung cancer (50).…”

Section: Discussionmentioning

confidence: 96%

The value of a group of serum miRNAs in screening prostate cancer

Sun

et al. 2022

Preprint

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Background Prostate cancer remains a worldwide public health problem that poses a serious threat to the health of men worldwide. Many studies have found that miRNA in serum has the possible to be a biomarker for cancer. Our study was conducted to investigate the valuation of serum miRNAs in prostate cancer screening. Methods We selected 12 miRNAs from past studies associated with prostate cancer. We checked the expression levels of these miRNAs in the serum of 112 prostate cancer patients and 112 healthy controls in a two-stage experiment. We plotted the receiver operating characteristic curve of miRNAs in the validation stage and constructed a four-miRNA panel with the highest diagnostic value using stepwise logistic regression. We also predicted the target genes for these four miRNAs through online databases and performed Gene Ontology functional annotation and pathway analysis. Results The results showed that 6 miRNAs (miR-429, miR-10a-5p, miR-183-5p, miR-181a-5p, miR-1231, miR-129-5p) were abnormally expressed in the serum of prostate cancer patients. We used four of these miRNAs including miR-1231, miR-10a-5p, miR-429 and miR-129-5p to construct a combination of miRNAs with high specificity and sensitivity in screening prostate cancer (area under the curve (AUC) = 0.878). Bioinformatic analysis has shown that the genes targeted by these miRNAs can be linked to the development of cancer. Conclusions Our study detected and identified a set of miRNAs that serve as screening markers for prostate cancer, which may assist in early diagnosis and treatment of prostate cancer.

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“…In addition, our study did not evaluate the potential role of NRG1 directly produced by cancer cells. In this regard, silencing of NRG1 in triple-negative cellular models has been very recently documented to reduce cell migration [ 54 ], further supporting a role for NRG1 signaling in basal-like/triple-negative cancers. Previously, NRG1 administration to MCF10A cells engineered with ERBB2 overexpression was demonstrated to induce an invasive phenotype with protruded arms when cultured in 3D conditions [ 32 ].…”

Section: Discussionmentioning

confidence: 98%

NRG1/ERBB3/ERBB2 Axis Triggers Anchorage-Independent Growth of Basal-like/Triple-Negative Breast Cancer Cells

Miano

Morselli

Pontis

et al. 2022

Cancers

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ERBB3, also known as HER3, is a tyrosine kinase transmembrane receptor of the ERBB family. Upon binding to neuregulin 1 (NRG1), ERBB3 preferentially dimerizes with HER2 (ERBB2), in turn inducing aggressive features in several cancer types. The analysis of a dataset of breast cancer patients unveiled that higher ERBB3 mRNA expression correlates with shorter relapse-free survival in basal-like breast cancers, despite low ERBB3 expression in this breast cancer subtype. Administration of neuregulin 1 beta (NRG1β) significantly affected neither cellular proliferation nor the basal migratory ability of basal-like/triple-negative quasi-normal MCF10A breast cells, cultured in mono-layer conditions. Furthermore, no significant regulation in cell morphology or in the expression of basal/myoepithelial and luminal markers was observed upon stimulation with NRG1β. In non-adherent conditions, NRG1β administration to MCF10A cells did not significantly influence cell survival; however, it robustly induced cell growth as spheroids (3D growth). Intriguingly, a remarkable upregulation of ERBB3 and ERBB2 protein abundance was observed in 3D compared to 2D cell cultures, and NRG1β-induced 3D cell growth was efficiently prevented by the anti-HER2 monoclonal antibody pertuzumab. Similar results were obtained by the analysis of basal-like/triple-negative breast cancer cellular models, MDA-MB-468 and MDA-MB-231 cells, in which NRG1β induced anchorage-independent cell growth that in turn was prevented or reduced by the simultaneous administration of anti-HER2 neutralizing antibodies. Finally, the ability of pertuzumab in suppressing NRG1β-induced 3D growth was also evaluated and confirmed in MCF10A engineered with HER2-overexpression. We suggest that the NRG1/ERBB3/ERBB2 pathway promotes the anchorage-independent growth of basal-like breast cancer cells. Importantly, we provide evidence that ERBB2 neutralization, in particular by pertuzumab, robustly inhibits this process. Our results pave the way towards the development of novel anticancer strategies for basal-like breast cancer patients based on the interception of the NRG1/ERBB3/ERBB2 signaling axis.

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NRG1 regulates Fra-1 transcription and metastasis of triple-negative breast cancer cells via the c-Myc ubiquitination as manipulated by ERK1/2-mediated Fbxw7 phosphorylation

Cited by 10 publications

References 31 publications

The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting

The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting

The value of a group of serum miRNAs in screening prostate cancer

NRG1/ERBB3/ERBB2 Axis Triggers Anchorage-Independent Growth of Basal-like/Triple-Negative Breast Cancer Cells

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