scholarly journals Decreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Iga K. Mieczkowska ◽  
Garyfallia Pantelaiou-Prokaki ◽  
Evangelos Prokakis ◽  
Geske E. Schmidt ◽  
Lukas C. Müller-Kirschbaum ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Targets ◽  
Epithelial To Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Therapy Resistance ◽  
Epigenetic Switch ◽  
Mesenchymal Transition ◽  
Chip Sequencing ◽  
Development Of Resistance ◽  
Basal Like Breast Cancer

AbstractBreast cancer (BC) is the most common cancer occurring in women but also rarely develops in men. Recent advances in early diagnosis and development of targeted therapies have greatly improved the survival rate of BC patients. However, the basal-like BC subtype (BLBC), largely overlapping with the triple-negative BC subtype (TNBC), lacks such drug targets and conventional cytotoxic chemotherapies often remain the only treatment option. Thus, the development of resistance to cytotoxic therapies has fatal consequences. To assess the involvement of epigenetic mechanisms and their therapeutic potential increasing cytotoxic drug efficiency, we combined high-throughput RNA- and ChIP-sequencing analyses in BLBC cells. Tumor cells surviving chemotherapy upregulated transcriptional programs of epithelial-to-mesenchymal transition (EMT) and stemness. To our surprise, the same cells showed a pronounced reduction of polycomb repressive complex 2 (PRC2) activity via downregulation of its subunits Ezh2, Suz12, Rbbp7 and Mtf2. Mechanistically, loss of PRC2 activity leads to the de-repression of a set of genes through an epigenetic switch from repressive H3K27me3 to activating H3K27ac mark at regulatory regions. We identified Nfatc1 as an upregulated gene upon loss of PRC2 activity and directly implicated in the transcriptional changes happening upon survival to chemotherapy. Blocking NFATc1 activation reduced epithelial-to-mesenchymal transition, aggressiveness, and therapy resistance of BLBC cells. Our data demonstrate a previously unknown function of PRC2 maintaining low Nfatc1 expression levels and thereby repressing aggressiveness and therapy resistance in BLBC.

scholarly journals Salt Inducible Kinase Signaling Networks: Implications for Acute Kidney Injury and Therapeutic Potential

2019 ◽  
Vol 20 (13) ◽  
pp. 3219 ◽  
Author(s):  
Mary Taub
Keyword(s):  
Acute Kidney Injury ◽  
Histone Deacetylases ◽  
Drug Targets ◽  
Epithelial To Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Regulatory Element ◽  
Kidney Injury ◽  
Mesenchymal Transition ◽  
Disease States ◽  
Element Binding Protein

A number of signal transduction pathways are activated during Acute Kidney Injury (AKI). Of particular interest is the Salt Inducible Kinase (SIK) signaling network, and its effects on the Renal Proximal Tubule (RPT), one of the primary targets of injury in AKI. The SIK1 network is activated in the RPT following an increase in intracellular Na+ (Na+in), resulting in an increase in Na,K-ATPase activity, in addition to the phosphorylation of Class IIa Histone Deacetylases (HDACs). In addition, activated SIKs repress transcriptional regulation mediated by the interaction between cAMP Regulatory Element Binding Protein (CREB) and CREB Regulated Transcriptional Coactivators (CRTCs). Through their transcriptional effects, members of the SIK family regulate a number of metabolic processes, including such cellular processes regulated during AKI as fatty acid metabolism and mitochondrial biogenesis. SIKs are involved in regulating a number of other cellular events which occur during AKI, including apoptosis, the Epithelial to Mesenchymal Transition (EMT), and cell division. Recently, the different SIK kinase isoforms have emerged as promising drug targets, more than 20 new SIK2 inhibitors and activators having been identified by MALDI-TOF screening assays. Their implementation in the future should prove to be important in such renal disease states as AKI.

scholarly journals Rac Inhibition As A Novel Therapeutic Strategy for EGFR/HER2 Targeted Therapy Resistant Breast Cancer

2020 ◽  
Author(s):  
Luis D Borrero-Garcia ◽  
Maria del Mar Maldonado ◽  
Julia I Medina-Velázquez ◽  
Angel Troche-Torres ◽  
Luis Velazquez-Vega ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Epithelial To Mesenchymal Transition ◽  
Point Mutations ◽  
Therapy Resistance ◽  
Small Gtpase ◽  
Mitogen Activated Protein Kinase ◽  
Intrinsic Resistance ◽  
Mesenchymal Transition ◽  
Resistant Cells

Abstract Background Even though targeted therapies are available for cancers expressing oncogenic epidermal growth receptor (EGFR) and (or) human EGFR2 (HER2), acquired or intrinsic resistance often confounds therapy success. Common mechanisms of therapy resistance involve activating receptor point mutations and (or) upregulation of signaling downstream of EGFR/HER2 to Akt and (or) mitogen activated protein kinase (MAPK) pathways. However, additional pathways of resistance may exist thus, confounding successful therapy. Methods To determine novel mechanisms of EGFR/HER2 therapy resistance in breast cancer, gefitinib or lapatinib resistant variants were created from SKBR3 breast cancer cells. Syngenic therapy sensitive and resistant SKBR3 variants were characterized for mechanisms of resistance by mammosphere assays, viability assays, and western blotting for total and phospho proteins. Results Gefitinib and lapatinib treatments reduced mammosphere formation in the parental cells, but not in the therapy resistant variants, indicating enhanced cancer stem cell-like and epithelial to mesenchymal transition (EMT) characteristics in therapy resistant cells. The therapy resistant variants did not show significant changes in established therapy resistant pathways of Akt and MAPK activities downstream of EGFR/HER2. However, these cells exhibited elevated expression and activation of the small GTPase Rac, which is a pivotal intermediate of GFR signaling in EMT and metastasis. Therefore, the potential of the Rac inhibitors EHop-016 and MBQ-167 to overcome therapy resistance was tested and found to inhibit viability and induce apoptosis of therapy resistant cells. Conclusions Rac inhibition may represent a viable strategy for treatment of EGFR/HER2 targeted therapy resistant breast cancer.

scholarly journals HDAC8 suppresses the epithelial phenotype and promotes EMT in chemotherapy-treated basal-like breast cancer

2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Garyfallia Pantelaiou-Prokaki ◽  
Iga Mieczkowska ◽  
Geske E. Schmidt ◽  
Sonja Fritzsche ◽  
Evangelos Prokakis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factors ◽  
Tumor Cells ◽  
Cell Phenotype ◽  
Cancer Resistance ◽  
Conventional Chemotherapy ◽  
Mesenchymal Transition ◽  
Chip Sequencing ◽  
Epithelial Phenotype ◽  
Basal Like Breast Cancer

Abstract Background Basal-like breast cancer (BLBC) is one of the most aggressive malignant diseases in women with an increased metastatic behavior and poor prognosis compared to other molecular subtypes of breast cancer. Resistance to chemotherapy is the main cause of treatment failure in BLBC. Therefore, novel therapeutic strategies counteracting the gain of aggressiveness underlying therapy resistance are urgently needed. The epithelial-to-mesenchymal transition (EMT) has been established as one central process stimulating cancer cell migratory capacity but also acquisition of chemotherapy-resistant properties. In this study, we aimed to uncover epigenetic factors involved in the EMT-transcriptional program occurring in BLBC cells surviving conventional chemotherapy. Results Using whole transcriptome data from a murine mammary carcinoma cell line (pG-2), we identified upregulation of Hdac4, 7 and 8 in tumor cells surviving conventional chemotherapy. Subsequent analyses of human BLBC patient datasets and cell lines established HDAC8 as the most promising factor sustaining tumor cell viability. ChIP-sequencing data analysis identified a pronounced loss of H3K27ac at regulatory regions of master transcription factors (TFs) of epithelial phenotype like Gata3, Elf5, Rora and Grhl2 upon chemotherapy. Interestingly, impairment of HDAC8 activity reverted epithelial-TFs levels. Furthermore, loss of HDAC8 activity sensitized tumor cells to chemotherapeutic treatments, even at low doses. Conclusion The current study reveals a previously unknown transcriptional repressive function of HDAC8 exerted on a panel of transcription factors involved in the maintenance of epithelial cell phenotype, thereby supporting BLBC cell survival to conventional chemotherapy. Our data establish HDAC8 as an attractive therapeutically targetable epigenetic factor to increase the efficiency of chemotherapeutics. Graphical abstract

scholarly journals Therapeutic Potential of a Novel αvβ3 Antagonist to Hamper the Aggressiveness of Mesenchymal Triple Negative Breast Cancer Sub-Type

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 139 ◽  
Author(s):  
Billy Hill ◽  
Annachiara Sarnella ◽  
Domenica Capasso ◽  
Daniela Comegna ◽  
Annarita Del Gatto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Triple Negative ◽  
Therapeutic Potential ◽  
Migration And Invasion ◽  
Αvβ3 Integrin ◽  
Altered Expression ◽  
Mesenchymal Transition

The mesenchymal sub-type of triple negative breast cancer (MES-TNBC) has a highly aggressive behavior and worse prognosis, due to its invasive and stem-like features, that correlate with metastatic dissemination and resistance to therapies. Furthermore, MES-TNBC is characterized by the expression of molecular markers related to the epithelial-to-mesenchymal transition (EMT) program and cancer stem cells (CSCs). The altered expression of αvβ3 integrin has been well established as a driver of cancer progression, stemness, and metastasis. Here, we showed that the high levels of αvβ3 are associated with MES-TNBC and therefore exploited the possibility to target this integrin to reduce the aggressiveness of this carcinoma. To this aim, MES-TNBC cells were treated with a novel peptide, named ψRGDechi, that we recently developed and characterized for its ability to selectively bind and inhibit αvβ3 integrin. Notably, ψRGDechi was able to hamper adhesion, migration, and invasion of MES-TNBC cells, as well as the capability of these cells to form vascular-like structures and mammospheres. In addition, this peptide reversed EMT program inhibits mesenchymal markers. These findings show that targeting αvβ3 integrin by ψRGDechi, it is possible to inhibit some of the malignant properties of MES-TNBC phenotype.

scholarly journals ERβ1 represses basal-like breast cancer epithelial to mesenchymal transition by destabilizing EGFR

2012 ◽  
Vol 14 (6) ◽  
Author(s):  
Christoforos Thomas ◽  
Gayani Rajapaksa ◽  
Fotis Nikolos ◽  
Ruixin Hao ◽  
Anne Katchy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Basal Like Breast Cancer

scholarly journals Long Non-Coding RNA: Dual Effects on Breast Cancer Metastasis and Clinical Applications

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1802 ◽  
Author(s):  
Qi-Yuan Huang ◽  
Guo-Feng Liu ◽  
Xian-Ling Qian ◽  
Li-Bo Tang ◽  
Qing-Yun Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Distant Metastasis ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Therapy Resistance ◽  
Breast Cancer Metastasis ◽  
Mesenchymal Transition ◽  
Non Coding Rna ◽  
Regulatory Effects ◽  
Long Non Coding Rna

As a highly heterogeneous malignancy, breast cancer (BC) has become the most significant threat to female health. Distant metastasis and therapy resistance of BC are responsible for most of the cases of mortality and recurrence. Distant metastasis relies on an array of processes, such as cell proliferation, epithelial-to-mesenchymal transition (EMT), mesenchymal-to-epithelial transition (MET), and angiogenesis. Long non-coding RNA (lncRNA) refers to a class of non-coding RNA with a length of over 200 nucleotides. Currently, a rising number of studies have managed to investigate the association between BC and lncRNA. In this study, we summarized how lncRNA has dual effects in BC metastasis by regulating invasion, migration, and distant metastasis of BC cells. We also emphasize that lncRNA has crucial regulatory effects in the stemness and angiogenesis of BC. Clinically, some lncRNAs can regulate chemotherapy sensitivity in BC patients and may function as novel biomarkers to diagnose or predict prognosis for BC patients. The exact impact on clinical relevance deserves further study. This review can be an approach to understanding the dual effects of lncRNAs in BC, thereby linking lncRNAs to quasi-personalized treatment in the future.

scholarly journals LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells

Oncogene ◽  
2015 ◽  
Vol 35 (22) ◽  
pp. 2932-2947 ◽  
Author(s):  
N Yokdang ◽  
J Hatakeyama ◽  
J H Wald ◽  
C Simion ◽  
J D Tellez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Basal Like Breast Cancer

scholarly journals Inferring latent temporal progression and regulatory networks from cross-sectional transcriptomic data of cancer samples

2021 ◽  
Vol 17 (3) ◽  
pp. e1008379 ◽  
Author(s):  
Xiaoqiang Sun ◽  
Ji Zhang ◽  
Qing Nie
Keyword(s):  
Breast Cancer ◽  
Bladder Cancer ◽  
Cancer Progression ◽  
Drug Targets ◽  
Regulatory Networks ◽  
Time Course ◽  
Epithelial To Mesenchymal Transition ◽  
Cross Sectional ◽  
Mesenchymal Transition ◽  
Transcriptomic Data

Unraveling molecular regulatory networks underlying disease progression is critically important for understanding disease mechanisms and identifying drug targets. The existing methods for inferring gene regulatory networks (GRNs) rely mainly on time-course gene expression data. However, most available omics data from cross-sectional studies of cancer patients often lack sufficient temporal information, leading to a key challenge for GRN inference. Through quantifying the latent progression using random walks-based manifold distance, we propose a latent-temporal progression-based Bayesian method, PROB, for inferring GRNs from the cross-sectional transcriptomic data of tumor samples. The robustness of PROB to the measurement variabilities in the data is mathematically proved and numerically verified. Performance evaluation on real data indicates that PROB outperforms other methods in both pseudotime inference and GRN inference. Applications to bladder cancer and breast cancer demonstrate that our method is effective to identify key regulators of cancer progression or drug targets. The identified ACSS1 is experimentally validated to promote epithelial-to-mesenchymal transition of bladder cancer cells, and the predicted FOXM1-targets interactions are verified and are predictive of relapse in breast cancer. Our study suggests new effective ways to clinical transcriptomic data modeling for characterizing cancer progression and facilitates the translation of regulatory network-based approaches into precision medicine.

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