LRH-1 controls proliferation in breast tumor cells by regulating CDKN1A gene expression

Bianco, Stéphanie; Jangal, Maïka; Garneau, Daniel; Gévry, Nicolas

doi:10.1038/onc.2014.382

Cited by 54 publications

(56 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…p21 is an important regulator of cell proliferation and survival in TNBC cells under various stimulatory pathways . We therefore examined p21 protein levels upon NFIB depletion.…”

Section: Resultsmentioning

confidence: 99%

NFIB promotes cell survival by directly suppressing p21 transcription in TP53‐mutated triple‐negative breast cancer

Liu

Jain

et al. 2018

The Journal of Pathology

View full text Add to dashboard Cite

Triple‐negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited treatment options and poor prognosis. There is an urgent need to identify and understand the key factors and signalling pathways driving TNBC tumour progression, relapse, and treatment resistance. In this study, we report that gene copy numbers and expression levels of nuclear factor IB (NFIB), a recently identified oncogene in small cell lung cancer, are preferentially increased in TNBC compared to other breast cancer subtypes. Furthermore, increased levels of NFIB are significantly associated with high tumour grade, poor prognosis, and reduced chemotherapy response. Concurrent TP53 mutations and NFIB overexpression (z‐scores > 0) were observed in 77.9% of TNBCs, in contrast to 28.5% in non‐TNBCs. Depletion of NFIB in TP53‐mutated TNBC cell lines promotes cell death, cell cycle arrest, and enhances sensitivity to docetaxel, a first‐line chemotherapeutic drug in breast cancer treatment. Importantly, these alterations in growth properties were accompanied by induction of CDKN1A, the gene encoding p21, a downstream effector of p53. We show that NFIB directly interacts with the CDKN1A promoter in TNBC cells. Furthermore, knockdown of combined p21 and NFIB reverses the docetaxel‐induced cell growth inhibition observed upon NFIB knockdown, indicating that NFIB's effect on chemotherapeutic drug response is mediated through p21. Our results indicate that NFIB is an important TNBC factor that drives tumour cell growth and drug resistance, leading to poor clinical outcomes. Thus, targeting NFIB in TP53‐mutated TNBC may reverse oncogenic properties associated with mutant p53 by restoring p21 activity. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

show abstract

“…p21 is an important regulator of cell proliferation and survival in TNBC cells under various stimulatory pathways . We therefore examined p21 protein levels upon NFIB depletion.…”

Section: Resultsmentioning

confidence: 99%

NFIB promotes cell survival by directly suppressing p21 transcription in TP53‐mutated triple‐negative breast cancer

Liu

Jain

et al. 2018

The Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…However, recent evidence has demonstrated important roles for NR5A2 in colon and pancreatic cancer postulated to be through hedgehog and Wnt/β-catenin signalling pathways60616263. In our study suppression of NR5A2 function by siRNA-mediated silencing or use of the CPD-3 antagonist, both resulted in significant growth arrest and detectable caspase3-mediated cleavage in OAC cells.…”

Section: Discussionmentioning

confidence: 46%

The characterization of an intestine-like genomic signature maintained during Barrett’s-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival

Duggan

Behan

Kirca

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Barrett’s oesophagus (BO), an intestinal-type metaplasia (IM), typically arising in conjunction with gastro-oesophageal reflux disease, is a prominent risk factor for the development of oesophageal adenocarcinoma (OAC). The molecular similarities between IM and normal intestinal tissues are ill-defined. Consequently, the contribution of intestine-enriched factors expressed within BO to oncogenesis is unclear. Herein, using transcriptomics we define the intestine-enriched genes expressed in meta-profiles of BO and OAC. Interestingly, 77% of the genes differentially expressed in a meta-profile of BO were similarly expressed in intestinal tissues. Furthermore, 85% of this intestine-like signature was maintained upon transition to OAC. Gene networking analysis of transcription factors within this signature revealed a network centred upon NR5A2, GATA6 and FOXA2, whose over-expression was determined in a cohort of BO and OAC patients. Simulated acid reflux was observed to induce the expression of both NR5A2 and GATA6. Using siRNA-mediated silencing and an NR5A2 antagonist we demonstrate that NR5A2-mediated cancer cell survival is facilitated through augmentation of GATA6 and anti-apoptotic factor BCL-XL levels. Abrogation of NR5A2-GATA6 expression in conjunction with BCL-XL co-silencing resulted in synergistically increased sensitivity to chemotherapeutics and photo-dynamic therapeutics. These findings characterize the intestine-like signature associated with IM which may have important consequences to adenocarcinogenesis.

show abstract

“…Crucially, emerging research has revealed that elevated LRH1 expression in pancreatic cancer affects epithelial‐mesenchymal transition (EMT) progression, pancreatic cancer stem cell (CSC) potential and tumor metastasis . In addition, LRH1 facilitates the invasion ability of breast cancer cells by either transforming the actin cytoskeleton or decreasing cyclin‐dependent kinase inhibitor (CDKN1A) transcription independent of ERα and p53 status . By targeting LRH1, the downregulation of miR‐30d is prominently associated with distant metastasis, poorer differentiation, advanced clinical tumor node metastasis (TNM) stage and lymph node metastasis, and promotes cell proliferation or invasion in colorectal carcinoma .…”

Section: Introductionmentioning

confidence: 99%

LRH1 as a promising prognostic biomarker and predictor of metastasis in patients with non‐small cell lung cancer

et al. 2018

View full text Add to dashboard Cite

BackgroundLRH1, which promotes the malignant transformation of carcinoma, has recently been documented in several types of malignancies. However, LRH1 has not been assessed as a potential clinical biomarker in any cancer.MethodsLRH1 expression was tested in fresh‐frozen tissue samples with quantitative real‐time PCR and Western blot analysis. Surgically resected tumor tissues were collected from 156 non‐small cell lung cancer (NSCLC) patients: 75 with adenocarcinoma and 81 with squamous cell carcinoma. Subsequently, the immunohistochemical expression of LRH1 was examined, and its clinical significance was evaluated.ResultsLRH1 overexpression was observed in NSCLC carcinoma tissues compared to adjacent normal lung tissues. LRH1 expression was correlated with poorer differentiation (P = 0.023), pathological tumor classification (P < 0.001), advanced pathological tumor node metastasis stage (P = 0.017), adenocarcinoma subtype (P = 0.031), and positive lymph node metastasis (P < 0.001). Multivariate analysis demonstrated that LRH1 expression status was an independent prognostic factor for overall (hazard ratio 1.372, 95% confidence interval 1.225–1.617; P = 0.003) and disease‐free survival (hazard ratio 1.497, 95% confidence interval 1.059–2.115; P = 0.011) in patients who suffered from resectable NSCLC.ConclusionThe results of our study indicate that LRH1 predicts NSCLC progression, metastasis, and a dismal prognosis, emphasizing its promising role as a novel target in NSCLC therapies.

show abstract

LRH-1 controls proliferation in breast tumor cells by regulating CDKN1A gene expression

Cited by 54 publications

References 53 publications

NFIB promotes cell survival by directly suppressing p21 transcription in TP53‐mutated triple‐negative breast cancer

NFIB promotes cell survival by directly suppressing p21 transcription in TP53‐mutated triple‐negative breast cancer

The characterization of an intestine-like genomic signature maintained during Barrett’s-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival

LRH1 as a promising prognostic biomarker and predictor of metastasis in patients with non‐small cell lung cancer

Contact Info

Product

Resources

About