scholarly journals METTL3 Depletion Contributes to HR+/HER2- Breast Cancer Progression and Drug Resistance via m6A Modification of Constituents of the CDKN1A/EMT and BAX/caspase-9/-3/-8 Signalling Pathways

2021 ◽  
Author(s):  
Dengjie Ouyang ◽  
Tao Hong ◽  
Mengdie Fu ◽  
Yitong Li ◽  
Liyun Zeng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Drug Sensitivity ◽  
Tumour Progression ◽  
Signalling Pathways ◽  
Caspase 9 ◽  
Her2 Breast Cancer ◽  
Potential Biomarker ◽  
Response To Chemotherapy ◽  
Mesenchymal Transformation

Abstract Background: Chemotherapy is an important strategy for the treatment of hormone receptor positive / human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer (BC), but this subtype has a low response to chemotherapy. Growing evidence indicates that N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells and that methyltransferase-like 3 (METTL3) participates in tumour progression in several cancer types. Therefore, exploring the function of METTL3 in HR+HER2- BC initiation and development is still significant.Methods: mRNA and protein expression levels were analysed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Cell proliferation was detected by CCK-8 assays, cell migration was analysed by wound healing assays, and apoptosis was analysed by TUNEL assays. Finally, m6A modification was analysed by methylated RNA immunoprecipitation (MeRIP).Results: Chemotherapy-induced downregulation of the m6A modification is regulated by METTL3 in HR+/HER2- BC. METTL3 knockdown in MCF-7/T47D cells weakened the drug sensitivity of HR+/HER2- BC cells by promoting tumour proliferation and metastasis and inhibiting apoptosis. Mechanistically, CDKN1A was subsequently recognized as a downstream target of METTL3 that activates the AKT pathway and promotes epithelial-mesenchymal transformation (EMT). Moreover, the RNA level of BAX was decreased due to a lower level of m6A modification mediated by METTL3, and apoptosis was inhibited by inactivation of caspase 3/9/8.Conclusion: METTL3 regulates the proliferation, migration, and drug sensitivity of HR+/HER2- BC via activation of the CDKN1A/EMT and m6A-BAX/caspase 9/3/8 signalling pathways, which suggests its role as a potential biomarker for predicting the prognosis of patients with HR+/HER2- BC.

scholarly journals METTL3 Depletion Contributes to HR+/HER2- Breast Cancer Progression and Drug Resistance via m6A Modification of Constituents of the CDKN1A/EMT and BAX/caspase-9/-3/-8 Signalling Pathways

2021 ◽  
Author(s):  
Dengjie Ouyang ◽  
Tao Hong ◽  
Mengdie Fu ◽  
Yitong Li ◽  
Liyun Zeng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Drug Sensitivity ◽  
Tumour Progression ◽  
Signalling Pathways ◽  
Caspase 9 ◽  
Her2 Breast Cancer ◽  
Potential Biomarker ◽  
Response To Chemotherapy ◽  
Mesenchymal Transformation

Abstract Background Chemotherapy is an important strategy for the treatment of hormone receptor positive / human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer (BC), but this subtype has a low response to chemotherapy. Growing evidence indicates that N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells and that methyltransferase-like 3 (METTL3) participates in tumour progression in several cancer types. Therefore, exploring the function of METTL3 in HR+HER2- BC initiation and development is still significant. Methods mRNA and protein expression levels were analysed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Cell proliferation was detected by CCK-8 assays, cell migration was analysed by wound healing assays, and apoptosis was analysed by TUNEL assays. Finally, m6A modification was analysed by methylated RNA immunoprecipitation (MeRIP). Results Chemotherapy-induced downregulation of the m6A modification is regulated by METTL3 in HR+/HER2- BC. METTL3 knockdown in MCF-7/T47D cells weakened the drug sensitivity of HR+/HER2- BC cells by promoting tumour proliferation and metastasis and inhibiting apoptosis. Mechanistically, CDKN1A was subsequently recognized as a downstream target of METTL3 that activates the AKT pathway and promotes epithelial-mesenchymal transformation (EMT). Moreover, the RNA level of BAX was decreased due to a lower level of m6A modification mediated by METTL3, and apoptosis was inhibited by inactivation of caspase 3/9/8. Conclusion METTL3 regulates the proliferation, migration, and drug sensitivity of HR+/HER2- BC via activation of the CDKN1A/EMT and m6A-BAX/caspase 9/3/8 signalling pathways, which suggests its role as a potential biomarker for predicting the prognosis of patients with HR+/HER2- BC.

scholarly journals Deregulation of protein phosphatase 2A inhibitor SET is associated with malignant progression in breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katsunori Tozuka ◽  
Pattama Wongsirisin ◽  
Shigenori E. Nagai ◽  
Yasuhito Kobayashi ◽  
Miki Kanno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Recurrent Breast Cancer ◽  
Stage I ◽  
Breast Cancer Patients ◽  
Potential Biomarker ◽  
Phosphatase 2A ◽  
Mcf 7

AbstractTo understand the mechanism underlying metastasis, identification of a mechanism-based and common biomarker for circulating tumour cells (CTCs) in heterogenous breast cancer is needed. SET, an endogenous inhibitor of protein phosphatase 2A, was overexpressed in all subtypes of invasive breast carcinoma tissues. Treatment with SET-targeted siRNAs reduced the motility of MCF-7 and MDA-MB-231 cells in transwell assay. SET knockdown reduced the number of mammospheres by 60–70% in MCF-7 and MDA-MB-231 cells, which was associated with the downregulation of OCT4 and SLUG. Hence, we analysed the presence of SET-expressing CTCs (SET-CTCs) in 24 breast cancer patients. CTCs were enriched using a size-based method and then immunocytochemically analysed using an anti-SET antibody. SET-CTCs were detected in 6/6 (100%) patients with recurrent breast cancer with a median value of 12 (12 cells/3 mL blood), and in 13/18 (72.2%) patients with stage I–III breast cancer with a median value of 2.5, while the median value of healthy controls was 0. Importantly, high numbers of SET-CTCs were correlated with lymph node metastasis in patients with stage I–III disease. Our results indicate that SET contributes to breast cancer progression and can act as a potential biomarker of CTCs for the detection of metastasis.

scholarly journals Towards establishing extracellular vesicle-associated RNAs as biomarkers for HER2+ breast cancer

F1000Research ◽  
2021 ◽  
Vol 9 ◽  
pp. 1362
Author(s):  
Colin L. Hisey ◽  
Petr Tomek ◽  
Yohanes N.S. Nursalim ◽  
Lawrence W. Chamley ◽  
Euphemia Leung
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Breast Tissue ◽  
Extracellular Vesicle ◽  
Rt Pcr ◽  
Serum Replacement ◽  
Her2 Breast Cancer ◽  
Meta Analyses ◽  
Rna Biomarkers

Extracellular vesicles (EVs) are emerging as key players in breast cancer progression and hold immense promise as cancer biomarkers. However, difficulties in obtaining sufficient quantities of EVs for the identification of potential biomarkers hampers progress in this area. To circumvent this obstacle, we cultured BT-474 breast cancer cells in a two-chambered bioreactor with CDM-HD serum replacement to significantly improve the yield of cancer cell-associated EVs and eliminate bovine EV contamination. Cancer-relevant mRNAs BIRC5 (Survivin) and YBX1, as well as long-noncoding RNAs HOTAIR, ZFAS1, and AGAP2-AS1 were detected in BT-474 EVs by quantitative RT-PCR. Bioinformatics meta-analyses showed that BIRC5 and HOTAIR RNAs were substantially upregulated in breast tumours compared to non-tumour breast tissue, warranting further studies to explore their usefulness as biomarkers in patient EV samples. We envision this effective procedure for obtaining large amounts of cancer-specific EVs will accelerate discovery of EV-associated RNA biomarkers for cancers including HER2+ breast cancer.

scholarly journals Towards establishing extracellular vesicle-associated RNAs as biomarkers for HER2+ breast cancer

F1000Research ◽  
2021 ◽  
Vol 9 ◽  
pp. 1362
Author(s):  
Colin L. Hisey ◽  
Petr Tomek ◽  
Yohanes N.S. Nursalim ◽  
Lawrence W. Chamley ◽  
Euphemia Leung
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Breast Tissue ◽  
Extracellular Vesicle ◽  
Rt Pcr ◽  
Serum Replacement ◽  
Her2 Breast Cancer ◽  
Meta Analyses ◽  
Rna Biomarkers

Extracellular vesicles (EVs) are emerging as key players in breast cancer progression and hold immense promise as cancer biomarkers. However, difficulties in obtaining sufficient quantities of EVs for the identification of potential biomarkers hampers progress in this area. To circumvent this obstacle, we cultured BT-474 breast cancer cells in a two-chambered bioreactor with CDM-HD serum replacement to significantly improve the yield of cancer cell-associated EVs and eliminate bovine EV contamination. Cancer-relevant mRNAs BIRC5 (Survivin) and YBX1, as well as long-noncoding RNAs HOTAIR, ZFAS1, and AGAP2-AS1 were detected in BT-474 EVs by quantitative RT-PCR. Bioinformatics meta-analyses showed that BIRC5 and HOTAIR RNAs were substantially upregulated in breast tumours compared to non-tumour breast tissue, warranting further studies to explore their usefulness as biomarkers in patient EV samples. We envision this effective procedure for obtaining large amounts of cancer-specific EVs will accelerate discovery of EV-associated RNA biomarkers for cancers including HER2+ breast cancer.

scholarly journals Mechanisms of Metastasis and Cell Mobility – The Role of Metabolism

2019 ◽  
Vol 79 (02) ◽  
pp. 184-188 ◽  
Author(s):  
Carsten Gründker ◽  
Matthias Läsche ◽  
Johanna Hellinger ◽  
Günter Emons
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Early Stage ◽  
Breast Cancer Patients ◽  
Metastatic Cascade ◽  
Cell Mobility ◽  
Tumour Metastasis ◽  
Multi Stage ◽  
Mesenchymal Transformation

AbstractTumour metastasis is responsible for more than 90% of tumour-associated mortality. About one third of breast cancer patients in the early stage develop metastases. The transformation in tumour development referred to as the “metastatic cascade” or “metastatic cycle” is a complex and multi-stage event. While it is generally recognised that epithelial-mesenchymal transformation (EMT) plays a crucial role in cancer progression and metastasis, the metabolic events in this process have received little attention to date. We would therefore like to provide a brief overview here of the influence of the metabolism on the progression and metastasis of tumours.

Protein tyrosine kinase 6 (PTK6, BRK) amplification in HER2+ breast cancer as a mechanism of HER2 resistance.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11021-11021
Author(s):  
Tatyana A. Grushko ◽  
Maria J. Gomez-Vega ◽  
Aleix Prat ◽  
Jeffrey Mueller ◽  
Mariann Coyle ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Mrna Expression ◽  
Cancer Progression ◽  
Gene Copy ◽  
Normal Epithelium ◽  
Cancer Data ◽  
Her2 Breast Cancer ◽  
Study Results

11021 Background: PTK6 gene on chromosome 20q13 encodes the intracellular non-receptor tyrosine kinase. Studies in vivo and in vitro revealed a role for PTK6 in cell proliferation and survival, particularly in HER2+ breast cancer cells suggesting that PTK6 may associate with the HER2 pathway and confer resistance to HER2-targeted therapy. PTK6 protein is frequently overexpressed in breast cancer, however, the mechanism(s) underlying PTK6 overexpression and its role in cancer remains unclear. To address this problem, we analyzed the frequency of PTK6 gene copy number variation (CNV) and expression in association with breast cancer subtypes. Methods: Retrospectiveparaffinsamples of invasive tumor and normal epithelium, and matching DCIS and metastases were mounted on TMA. PTK6 CNV was determined using PTK6:CEP20 FISH assay. Tumor subtypes were defined using the five-marker IHC classifier. The correlation between PTK6 CNV and mRNA expression and association of both with the intrinsic PAM50 tumor subtype were studied using TCGA database (547 cases) and publicly available seven breast cancer data sets (1005 cases). Data were normalized, gene median centered and standardized for the purpose of the study. Results: By FISH, 20% of 41 invasive tumors carried PTK6 CNV: amplification (10%) and gene polysomy (10%). The proportion of PTK6 amplified cases differed by subtype, with the largest proportion in HER2-enriched (17%) and LumB (14%). Strikingly, amplified invasive cases also showed amplification in matching DCIS and metastases. Analysis of the public datasets confirmed the frequent PTK6 amplification in breast cancer. Both low and high levels of amplification were detected with the largest proportion in HER2+ tumors (HER2-enriched and LumB; p=2.05e-26). None of the basal-like tumors showed high levels of PTK6 amplification. A high correlation between PTK6 gene copies and mRNA expression was observed (p=1.13e-08). Conclusions: PTK6 gene is amplified early in breast cancer progression, particularly in HER2+ tumors. Further studies on PTK6 biology may help clinicians to understand its potential role in HER2 resistance. Supported by BREAST CANCER SPORE, NCI K12CA139160 and CTSA-ITM CS UL1 RR024999.

The short and the long: non-coding RNAs and growth factors in cancer progression

2017 ◽  
Vol 45 (1) ◽  
pp. 51-64 ◽  
Author(s):  
Aldema Sas-Chen ◽  
Swati Srivastava ◽  
Yosef Yarden
Keyword(s):  
Growth Factors ◽  
Cancer Progression ◽  
Tumour Progression ◽  
Therapeutic Strategies ◽  
Signalling Pathways ◽  
Circulation System ◽  
Multistep Process ◽  
New Locations ◽  
Non Coding Rnas ◽  
Lines Of Evidence

A relatively well-understood multistep process enables mutation-bearing cells to form primary tumours, which later use the circulation system to colonize new locations and form metastases. However, in which way the emerging abundance of different non-coding RNAs supports tumour progression is poorly understood. Here, we review new lines of evidence linking long and short types of non-coding RNAs to signalling pathways activated in the course of cancer progression by growth factors and by the tumour micro-environment. Resolving the new dimension of non-coding RNAs in oncogenesis will probably translate to earlier detection of cancer and improved therapeutic strategies.

scholarly journals Towards establishing Extracellular Vesicle-associated RNAs as biomarkers for HER2+ breast cancer

2020 ◽  
Author(s):  
Colin L. Hisey ◽  
Petr Tomek ◽  
Yohanes N.S. Nursalim ◽  
Lawrence W. Chamley ◽  
Euphemia Leung
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Breast Tissue ◽  
Extracellular Vesicle ◽  
Rt Pcr ◽  
Serum Replacement ◽  
Her2 Breast Cancer ◽  
Meta Analyses ◽  
Rna Biomarkers

AbstractExtracellular vesicles (EVs) are emerging as key players in breast cancer progression and hold immense promise as cancer biomarkers. However, difficulties in obtaining sufficient quantities of EVs for the identification of potential biomarkers hampers progress in this area. To circumvent this obstacle, we cultured BT-474 breast cancer cells in a two chambered bioreactor with CDM-HD serum replacement to significantly improve the yield of cancer cell-associated EVs and eliminate bovine EV contamination. Cancer-relevant mRNAs BIRC5 (Survivin) and YBX1 as well as long-noncoding RNAs HOTAIR, ZFAS1, and AGAP2-AS1 were detected in BT-474 EVs by quantitative RT-PCR. Bioinformatics meta-analyses showed that BIRC5 and HOTAIR RNAs were substantially upregulated compared to non-tumour breast tissue, encouraging further studies to explore their usefulness as biomarkers in patient EV samples. We contend that this effective procedure for obtaining large amounts of cancer-specific EVs will accelerate discovery of EV-associated RNA biomarkers for detection of HER2+ breast cancer.

scholarly journals Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer

2017 ◽  
Author(s):  
Lucy Ireland ◽  
Almudena Santos ◽  
Fiona Campbell ◽  
Carlos Figueiredo ◽  
Lesley Ellies ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factors ◽  
Cancer Progression ◽  
Invasive Breast Cancer ◽  
Metastatic Breast ◽  
Advanced Tumor Stage ◽  
Breast Cancer Patients ◽  
Advanced Tumor ◽  
Potential Biomarker ◽  
Insulin Like Growth Factors

ABSTRACTBreast cancer remains the leading cause of cancer death in women due to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumours. 75% of breast cancer patients show activation of Insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in a pre-clinical breast cancer model compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation.

scholarly journals Hsa-miR-21-3p associates with breast cancer patient survival and targets genes in tumor suppressive pathways

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260327
Author(s):  
Arsalan Amirfallah ◽  
Hildur Knutsdottir ◽  
Adalgeir Arason ◽  
Bylgja Hilmarsdottir ◽  
Oskar T. Johannsson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Cancer Progression ◽  
Target Genes ◽  
Independent Study ◽  
Cancer Specific Survival ◽  
Mesenchymal Transition ◽  
Pathological Characteristics ◽  
Large Breast ◽  
Potential Biomarker

Breast cancer is the cancer most often diagnosed in women. MicroRNAs (MIRs) are short RNA molecules that bind mRNA resulting in their downregulation. MIR21 has been shown to be an oncomiR in most cancer types, including breast cancer. Most of the effects of miR-21 have been attributed to hsa-miR-21-5p that is transcribed from the leading strand of MIR21, but hsa-miR-21-3p (miR-21-3p), transcribed from the lagging strand, is much less studied. The aim of the study is to analyze whether expression of miR-21-3p is prognostic for breast cancer. MiR-21-3p association with survival, clinical and pathological characteristics was analyzed in a large breast cancer cohort and validated in three separate cohorts, including TCGA and METABRIC. Analytical tools were also used to infer miR-21-3p function and to identify potential target genes and functional pathways. The results showed that in the exploration cohort, high miR-21-3p levels associated with shorter survival and lymph node positivity. In the three validation cohorts, high miR-21-3p levels associated with pathological characteristics that predict worse prognosis. Specifically, in the largest validation cohort, METABRIC (n = 1174), high miR-21-3p levels associated with large tumors, a high grade, lymph node and HER2 positivity, and shorter breast-cancer-specific survival (HR = 1.38, CI 1.13–1.68). This association remained significant after adjusting for confounding factors. The genes with expression levels that correlated with miR-21-3p were enriched in particular pathways, including the epithelial-to-mesenchymal transition and proliferation. Among the most significantly downregulated targets were MAT2A and the tumor suppressive genes STARD13 and ZNF132. The results from this study emphasize that both 3p- and 5p-arms from a MIR warrant independent study. The data show that miR-21-3p overexpression in breast tumors is a marker of worse breast cancer progression and it affects genes in pathways that drive breast cancer by down-regulating tumor suppressor genes. The results suggest miR-21-3p as a potential biomarker.

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