scholarly journals Epithelial to Mesenchymal Transition Regulates Surface PD-L1 via CMTM6 and CMTM7 Induction in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1165
Author(s):  
Malina Xiao ◽  
Meriem Hasmim ◽  
Audrey Lequeux ◽  
Kris Van Moer ◽  
Tuan Zea Tan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Surface ◽  
Epithelial To Mesenchymal Transition ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Aggressive Breast Cancer

CMTM6 is a critical regulator of cell surface expression of PD-L1 in tumor cells, but little is known about the transcriptional regulation of CMTM6. Here we report that the expression of CMTM6 positively correlates with the epithelial to mesenchymal transition (EMT) score in breast cancer cell lines and with the major EMT marker Vimentin in triple-negative breast cancers (TNBC). We showed that CMTM6 is concomitantly overexpressed with PD-L1 in breast mesenchymal compared with the epithelial cells. Driving a mesenchymal phenotype in SNAI1-inducible MCF-7 cells (MCF-7Mes cells) increased both PD-L1 and CMTM6. CMTM6 silencing in MCF-7Mes cells partially reduced cell surface expression of PD-L1, indicating that a proportion of the PD-L1 on the surface of MCF-7Mes cells depends on CMTM6. We also found a positive correlation between CMTM3 and CMTM7 expression with EMT score in breast cancer cells, and with Vimentin in TNBC patients. Dual knockdown of CMTM6 and CMTM7 significantly decreased PD-L1 surface expression in MCF-7Mes cells, indicating that both CMTM6 and CMTM7 regulate the expression of PD-L1. This study highlights the importance of CMTM6 and CMTM7 in EMT-induced PD-L1 and suggests that EMT, CMTM6 or CMTM7 modulators can be combined with anti-PD-L1 in patients with highly aggressive breast cancer.

scholarly journals DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer

2018 ◽  
Vol 115 (51) ◽  
pp. E11978-E11987 ◽  
Author(s):  
Ryoichi Matsunuma ◽  
Doug W. Chan ◽  
Beom-Jun Kim ◽  
Purba Singh ◽  
Airi Han ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Negative Feedback ◽  
Epithelial To Mesenchymal Transition ◽  
Triple Negative ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Multinucleated Cells ◽  
P21 Activated Kinase ◽  
Emt Markers ◽  
Mitotic Defect

A Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomic analysis prioritized dihydropyrimidinase-like-3 (DPYSL3) as a multilevel (RNA/protein/phosphoprotein) expression outlier specific to the claudin-low (CLOW) subset of triple-negative breast cancers. A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive (DPYSL3+) CLOW cell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition (EMT) markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative (DPYSL3−) CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2 (PAK2)-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT.

A Hidden Human Proteome Signature Characterizes the Epithelial Mesenchymal Transition Program

2020 ◽  
Vol 26 (3) ◽  
pp. 372-375 ◽  
Author(s):  
Daniele Vergara ◽  
Tiziano Verri ◽  
Marina Damato ◽  
Marco Trerotola ◽  
Pasquale Simeone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Open Reading Frames ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition ◽  
Cellular Models ◽  
Genomic Regions ◽  
Protein Signature

Background: Molecular changes associated with the initiation of the epithelial to mesenchymal transition (EMT) program involve alterations of large proteome-based networks. The role of protein products mapping to non-coding genomic regions is still unexplored. Objective: The goal of this study was the identification of an alternative protein signature in breast cancer cellular models with a distinct expression of EMT markers. Methods: We profiled MCF-7 and MDA-MB-231 cells using liquid-chromatography mass/spectrometry (LCMS/ MS) and interrogated the OpenProt database to identify novel predicted isoforms and novel predicted proteins from alternative open reading frames (AltProts). Results: Our analysis revealed an AltProt and isoform protein signature capable of classifying the two breast cancer cell lines. Among the most highly expressed alternative proteins, we observed proteins potentially associated with inflammation, metabolism and EMT. Conclusion: Here, we present an AltProts signature associated with EMT. Further studies will be needed to define their role in cancer progression.

scholarly journals Pannexin1 Is Associated with Enhanced Epithelial-To-Mesenchymal Transition in Human Patient Breast Cancer Tissues and in Breast Cancer Cell Lines

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1967 ◽  
Author(s):  
Nour Jalaleddine ◽  
Layal El-Hajjar ◽  
Hassan Dakik ◽  
Abdullah Shaito ◽  
Jessica Saliba ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Communication ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition ◽  
Genetic Ablation ◽  
Functional Features

Loss of connexin-mediated cell-cell communication is a hallmark of breast cancer progression. Pannexin1 (PANX1), a glycoprotein that shares structural and functional features with connexins and engages in cell communication with its environment, is highly expressed in breast cancer metastatic foci; however, PANX1 contribution to metastatic progression is still obscure. Here we report elevated expression of PANX1 in different breast cancer (BRCA) subtypes using RNA-seq data from The Cancer Genome Atlas (TCGA). The elevated PANX1 expression correlated with poorer outcomes in TCGA BRCA patients. In addition, gene set enrichment analysis (GSEA) revealed that epithelial-to-mesenchymal transition (EMT) pathway genes correlated positively with PANX1 expression. Pharmacological inhibition of PANX1, in MDA-MB-231 and MCF-7 breast cancer cells, or genetic ablation of PANX1, in MDA-MB-231 cells, reverted the EMT phenotype, as evidenced by decreased expression of EMT markers. In addition, PANX1 inhibition or genetic ablation decreased the invasiveness of MDA-MB-231 cells. Our results suggest PANX1 overexpression in breast cancer is associated with a shift towards an EMT phenotype, in silico and in vitro, attributing to it a tumor-promoting effect, with poorer clinical outcomes in breast cancer patients. This association offers a novel target for breast cancer therapy.

scholarly journals Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

2016 ◽  
Vol 113 (45) ◽  
pp. 12780-12785 ◽  
Author(s):  
Andrey S. Dobroff ◽  
Sara D’Angelo ◽  
Bedrich L. Eckhardt ◽  
Fortunato Ferrara ◽  
Daniela I. Staquicini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Surface ◽  
Antibody Fragment ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Binding Motif ◽  
Human Antibody ◽  
Surface Receptors ◽  
Cancer Phenotypes

Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.

scholarly journals Induced Tamoxifen Resistance is Mediated by Increased Methylation of E-Cadherin in Estrogen Receptor-Expressing Breast Cancer Cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Qi Wang ◽  
Melisa Gun ◽  
Xing-yu Hong
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Tamoxifen Resistant ◽  
Mcf 7 ◽  
E Cadherin

Abstract Estrogen receptor-positive breast cancers are treated with tamoxifen, a drug that competitively inhibits the binding of estrogen to its receptor. Resistance to tamoxifen is a major hurdle in effective management of target breast cancer patient population. A number of dynamic changes within the tumor microenvironment, including the phenomenon of epithelial to mesenchymal transition (EMT), determine the response to endocrine therapy. EMT is marked by silencing or suppression of epithelial marker, E-Cadherin and we found significantly down-regulated E-Cadherin, among other epithelial markers, and a significantly up-regulated mesenchymal marker, Twist, among other mesenchymal markers, in a model system that comprised of tamoxifen sensitive MCF-7 cells and their tamoxifen-resistant counterparts, MCF-7-TAM, developed by chronic and escalating exposure of parental cells to tamoxifen. Further, E-cadherin, but not Twist, was differentially expressed in MCF-7-TAM cells because of differential methylation. Treatment with demethylating agent 5-azacytidine increased the expression of E-cadherin thus verifying a role of methylation in its silencing and, moreover, 5-azacytidine treatment also re-sensitized MCF-7-TAM cells to tamoxifen, as evaluated by assays for viability, apoptosis and migration potential. The 5-azacytidine effects were similar to effects of E-cadherin overexpression in MCF-7-TAM cells. This work describes novel mechanism of E-cadherin downregulation in tamoxifen resistant breast cancer cells. Further studies are needed to exploit this information for betterment of breast cancer therapy.

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