scholarly journals Reduced menin expression leads to decreased ERα expression and is correlated with the occurrence of human luminal B-like and ER-negative breast cancer subtypes

2021 ◽  
Author(s):  
Romain Teinturier ◽  
Razan Abou Ziki ◽  
Loay Kassem ◽  
Yakun Luo ◽  
Lucie Malbeteau ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Reporter Gene ◽  
Breast Cancer Subtypes ◽  
Breast Cancers ◽  
Human Breast ◽  
Mcf7 Cells ◽  
Cancer Subtypes ◽  
Luminal B

Abstract Purpose Menin, encoded by the MEN1 gene, was recently reported to be involved in breast cancers, though the underlying mechanisms remain elusive. In the current study, we sought to further determine its role in mammary cells. Methods Menin expression in mammary lesions from mammary-specific Men1 mutant mice was detected using immunofluorescence staining. RT-qPCR and western blot were performed to determine the role of menin in ERα expression in human breast cancer cell lines. ChIP-qPCR and reporter gene assays were carried out to dissect the action of menin on the proximal ESR1 promoter. Menin expression in female patients with breast cancer was analyzed and its correlation with breast cancer subtypes was investigated. Results Immunofluorescence staining revealed that early mammary neoplasia in Men1 mutant mice displayed weak ERα expression. Furthermore, MEN1 silencing led to both reduced ESR1 mRNA and ERα protein expression in MCF7 and T47D cells. To further dissect the regulation of ESR1 transcription by menin, we examined whether and in which way menin could regulate the proximal ESR1 promoter, which has not been fully explored. Using ChIP analysis and reporter gene assays covering − 2500 bp to + 2000 bp of the TSS position, we showed that the activity of the proximal ESR1 promoter was markedly reduced upon menin downregulation independently of H3K4me3 status. Importantly, by analyzing the expression of menin in 354 human breast cancers, we found that a lower expression was associated with ER-negative breast cancer (P = 0.041). Moreover, among the 294 ER-positive breast cancer samples, reduced menin expression was not only associated with larger tumors (P = 0.01) and higher SBR grades (P = 0.005) but also with the luminal B-like breast cancer subtype (P = 0.006). Consistent with our clinical data, we demonstrated that GATA3 and FOXA1, co-factors in ESR1 regulation, interact physically with menin in MCF7 cells, and MEN1 knockdown led to altered protein expression of GATA3, the latter being a known marker of the luminal A subtype, in MCF7 cells. Conclusion Taken together, our data provide clues to the important role of menin in ERα regulation and the formation of breast cancer subtypes.

scholarly journals Ki67 index in intrinsic breast cancer subtypes and its association with prognostic parameters

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Atif Ali Hashmi ◽  
Kashif Ali Hashmi ◽  
Muhammad Irfan ◽  
Saadia Mehmood Khan ◽  
Muhammad Muzzammil Edhi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ductal Carcinoma ◽  
Prognostic Significance ◽  
Breast Cancer Subtypes ◽  
Prognostic Parameters ◽  
Ki67 Index ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Luminal B ◽  
Cancer Management

Abstract Objectives Ki67 is the most commonly used marker to evaluate proliferative index in breast cancer, however no cutoff values have been clearly defined for high ki67 index. Cancer management should be according to loco-regional profile; therefore, we aimed to determine ki67 index in 1951 cases of intrinsic breast cancer subtypes and its association with other prognostic parameters in our set up. Results Triple negative breast cancers showed highest ki67 index (mean 50.9 ± 23.7%) followed by Her2neu (mean 42.6 ± 21.6%) and luminal B cancers (mean 34.9 ± 20.05%). Metaplastic and medullary breast cancers significantly showed higher ki67 index as compared to ductal carcinoma, NOS. No significant association of ki67 index was noted with any of the histologic parameters in different subtypes of breast cancer expect for tumor grade. Although, ki67 index is a valuable biomarker in breast cancer, however no independent prognostic significance of ki67 could be established in our study.

scholarly journals Evaluation of FGFR targeting in breast cancer through interrogation of patient-derived models

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Nicole J. Chew ◽  
Terry C. C. Lim Kam Sian ◽  
Elizabeth V. Nguyen ◽  
Sung-Young Shin ◽  
Jessica Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapeutic Target ◽  
Breast Cancer Subtype ◽  
Breast Cancer Subtypes ◽  
Cancer Tissue ◽  
Breast Cancers ◽  
Luminal A ◽  
Tissue Samples ◽  
Cancer Subtypes ◽  
Luminal B

Abstract Background Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor–stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs. Methods MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival. Results Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated ‘omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target. Conclusions This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.

scholarly journals A combined approach with gene-wise normalization improves the analysis of RNA-seq data in human breast cancer subtypes

PLoS ONE ◽  
2018 ◽  
Vol 13 (8) ◽  
pp. e0201813 ◽  
Author(s):  
Xiaohong Li ◽  
Eric C. Rouchka ◽  
Guy N. Brock ◽  
Jun Yan ◽  
Timothy E. O’Toole ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Breast Cancer Subtypes ◽  
Combined Approach ◽  
Rna Seq ◽  
Human Breast ◽  
Cancer Subtypes

scholarly journals Role of DCE-MR imaging of the breast in predicting breast cancer subtypes: where are we going?

2017 ◽  
Vol 28 ◽  
pp. vi33
Author(s):  
L. Bastianelli ◽  
M. Pistelli ◽  
G.M. Giuseppetti ◽  
M. De Lisa ◽  
M. Macchini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mr Imaging ◽  
Breast Cancer Subtypes ◽  
Cancer Subtypes

Abstract B45: Epigenetic signature of human breast cancer subtypes

2009 ◽  
Author(s):  
Sunita Badola ◽  
Alexander Parker ◽  
Mara Campbel ◽  
Michael Boedigheimer ◽  
Barbara Grubinska ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Breast Cancer Subtypes ◽  
Human Breast ◽  
Cancer Subtypes

scholarly journals Cathepsin V suppresses GATA3 protein expression in luminal A breast cancer

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Naphannop Sereesongsaeng ◽  
Sara H. McDowell ◽  
James F. Burrows ◽  
Christopher J. Scott ◽  
Roberta E. Burden
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Cell Line ◽  
Cysteine Protease ◽  
Breast Cancers ◽  
Gata3 Expression ◽  
Er Positive ◽  
Cathepsin V ◽  
Gata3 Protein

Abstract Background Lysosomal cysteine protease cathepsin V has previously been shown to exhibit elevated expression in breast cancer tissue and be associated with distant metastasis. Research has also identified that cathepsin V expression is elevated in tumour tissues from numerous other malignancies, but despite this, there has been limited examination of the function of this protease in cancer. Here we investigate the role of cathepsin V in breast cancer in order to delineate the molecular mechanisms by which this protease contributes to tumourigenesis. Methods Lentiviral transductions were used to generate shRNA cell line models, with cell line validation undertaken using RQ-PCR and Western blotting. Phenotypic changes of tumour cell biology were examined using clonogenic and invasion assays. The relationship between GATA3 expression and cathepsin V was primarily analysed using Western blotting. Site-directed mutagenesis was used to generate catalytic mutant and shRNA-resistant constructs to confirm the role of cathepsin V in regulating GATA3 expression. Results We have identified that elevated cathepsin V expression is associated with reduced survival in ER-positive breast cancers. Cathepsin V regulates the expression of GATA3 in ER-positive breast cancers, through promoting its degradation via the proteasome. We have determined that depletion of cathepsin V results in elevated pAkt-1 and reduced GSK-3β expression, which rescues GATA3 from proteasomal degradation. Conclusions In this study, we have identified that cysteine protease cathepsin V can suppress GATA3 expression in ER-positive breast cancers by facilitating its turnover via the proteasome. Therefore, targeting cathepsin V may represent a potential therapeutic strategy in ER-positive breast cancers, by restoring GATA3 protein expression, which is associated with a more favourable clinical outcome.

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