scholarly journals TET2-mediated epigenetic reprogramming of breast cancer cells impairs lysosome biogenesis

2021 ◽  
Author(s):  
Audrey Laurent ◽  
Thierry Madigou ◽  
Maud Bizot ◽  
Marion Turpin ◽  
Gaëlle Palierne ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Catalytic Domain ◽  
Specific Gene ◽  
Lysosomal Storage ◽  
Binding Motifs ◽  
Lysosome Biogenesis ◽  
The One ◽  
And Function

Methylation and demethylation of cytosines in DNA are believed to act as keystones of cell-specific gene expression through controlling chromatin structure and accessibility to transcription factors. Cancer cells have their own transcriptional programs and we sought to alter such a cancer-specific program by enforcing expression of the catalytic domain (CD) of the methylcytosine dioxygenase TET2 in breast cancer cells. TET2 CD decreased the tumorigenic potential of cancer cells through both activation and repression of a repertoire of genes that, interestingly, differed in part from the one observed upon treatment with the hypomethylating agent decitabine. In addition to promoting the establishment of an antiviral state, TET2 activated 5mC turnover at thousands of MYC binding motifs and down-regulated a panel of known MYCrepressed genes involved in lysosome biogenesis and function. Thus, an extensive cross-talk between TET2 and the oncogenic transcription factor MYC establishes a lysosomal storage disease-like state that contributes to an exacerbated sensitivity to autophagy inducers.

scholarly journals Mannose glycosylation is an integral step for NIS localization and function in human breast cancer cells

2019 ◽  
Vol 132 (20) ◽  
pp. jcs232058 ◽  
Author(s):  
Maitreyi Rathod ◽  
Sushmita Chatterjee ◽  
Shruti Dutta ◽  
Rajiv Kalraiya ◽  
Dibyendu Bhattacharyya ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
And Function

The underlying mechanism contributing to P-gp over-expression and drug resistance in the MCF-7 breast cancer cells induced by adriamycin.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12028-e12028
Author(s):  
Guangji Wang ◽  
Jiye Aa ◽  
Chun Ge
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Underlying Mechanism ◽  
Ros Generation ◽  
Down Regulation ◽  
Over Expression ◽  
And Function ◽  
Mcf 7

e12028 Background: Continuous exposure of breast cancer cells to adriamycin (ADR) induces the over-expression of P-glycoprotein (P-gp) and multiple drug resistance. However, the biochemical process and underlying mechanisms are not clear. Our previous study revealed that ADR increased reactive oxygen species (ROS) generation and reduced glutathione (GSH) biosynthesis, while N-acetylcysteine, the ROS scavenger, reversed the over-expressed P-gp induced by ADR. Methods: Based on MCF-7 breast cancer cells and the adriamycin-resistant MCF-7 subline (MCF-7R), we investigated the P-gp expression on mRNA, protein and function level by qPCR, western blotting, flow cytometry and laser scanning confocal and so on, under SLC7A11 down-regulation/over-expression, cystine depletion/supplement, increased ROS generation and combined factors. Results: The present study showed that ADR inhibited cystine influx (source material of GSH) and SLC7A11 transporter (in charge of cystine uptake) in MCF-7 cells. For the first time, we showed that a down-regulation/silence of SLC7A11, or cystine deprivation, or an enhanced exposure of ROS agents directly and significantly increased P-gp expression; yet, a combination of either an inhibited/silenced SLC7A11 or cystine deprivation and an increased ROS dramatically promoted the P-gp expression in MCF-7 cells. On the contrary, an over-expression of SLC7A11, or sufficiently supplementary cystine, or scavenger of ROS significantly depressed P-gp expression and activity. Moreover, the down-regulation of SLC7A11 and cystine deprivation induced an elevation of ROS and P-gp that could be reversed by N-acetylcysteine. It was suggested that ROS and SLC7A11/cystine were the two relevant factors responsible for the upregulated expression and function of P-gp. Conclusions: This study provided the direct evidences suggesting that ROS triggered over-expression of P-gp and demonstrated that the combination of either an inhibition of SLC7A11 or cystine influx and elevated ROS was the underlying mechanism contributing to P-gp over-expression induced by ADR. It was indicated that the SLC7A11 might be a potential target modulating ADR resistance.

The enrichment of CD44 in exosomes from breast cancer cells treated with doxorubicin promotes chemoresistance

2020 ◽  
Author(s):  
xiaohong wang ◽  
kai cheng ◽  
guoqiang zhang ◽  
yue yu ◽  
song liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Chemotherapy Resistance ◽  
Clinical Samples ◽  
Cd44 Expression ◽  
Candidate Target ◽  
And Function ◽  
Cancer Chemoresistance ◽  
Mcf 7

Abstract Background: Exosomes have been shown to be associated with chemotherapy resistance transmission between cancer cells. However, the cargo and function of exosomes changed in response to doxorubicin remains unclear. Methods: We compared proteome profiles of exosomes extracted from the supernatant of MCF-7(S/Exo) and MCF-7/ADR(A/Exo) cells. We confirmed the differential expression of the candidate target-exosomic-CD44 by immune gold staining and western blot. We further studied the changes of chemosensitivity and CD44 expression in MCF-7 cells co-incubated with A/Exo. We analyzed the levels of exosomal CD44 from patient plasma, and compared the sensitivity and specificity of exosomic CD44 and plasma CD44 on diagnosis of chemoresistance. We modified the MCF-7-derived exosomes loaded with siRNA against CD44 to observe the effects of targeting reduced CD44 expression in lumimal A breast cancer cells. Results: DOX increased the exosomes release from MCF-7/ADR cells and the exosomes mediated proteins intercellular transfer in breast cancer chemoresistance regulation. The candidate target of CD44 in A/Exo was much higher than in S/Exo and the increase levels of exosomic CD44 (21.65-fold) was much higher than cellular CD44 (6.55-fold). The same results were obtained in clinical samples. Exosome-siRNA targeted CD44 (Exos-siCD44) could efficiently targeted to silence its expression. When co-cultured on Exos-siCD44, breast cancer cells exhibited reduced cell proliferation and enhanced susceptibility to DOX and the same phenomenon was observed in mice. Conclusion：Drug-resistant breast cancer cells spread resistance capacity to sensitive ones by releasing exosomes to transfer proteins in intercellular.

scholarly journals Discovery of Targeting Ligands for Breast Cancer Cells Using the One-Bead One-Compound Combinatorial Method

2009 ◽  
Vol 52 (1) ◽  
pp. 126-133 ◽  
Author(s):  
Nianhuan Yao ◽  
Wenwu Xiao ◽  
Xiaobing Wang ◽  
Jan Marik ◽  
See Hyoung Park ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Combinatorial Method ◽  
The One

Unliganded and Liganded Estrogen Receptors Protect against Cancer Invasion via Different Mechanisms

2000 ◽  
Vol 14 (7) ◽  
pp. 999-1009 ◽  
Author(s):  
Nadine Platet ◽  
Séverine Cunat ◽  
Dany Chalbos ◽  
Henri Rochefort ◽  
Marcel Garcia
Keyword(s):  
Breast Cancer ◽  
Amino Acids ◽  
Dna Binding ◽  
Cancer Cells ◽  
Zinc Finger ◽  
Transcriptional Activation ◽  
Breast Cancer Cells ◽  
Cancer Invasion ◽  
Specific Gene ◽  
Matrigel Invasion

Abstract While estrogens are mitogenic in breast cancer cells, the presence of estrogen receptor α (ERα) clinically indicates a favorable prognosis in breast carcinoma. To improve our understanding of ERα action in breast cancer, we used an original in vitro method, which combines transient transfection and Matrigel invasion assays to examine its effects on cell invasiveness. ERα expression in MDA-MB-231 breast cancer cells reduced their invasiveness by 3-fold in the absence of hormone and by 7-fold in its presence. Integrity of hormone and DNA-binding domains and activating function 2 were required for estradiol-induced inhibition, suggesting that transcriptional activation of estrogen target genes was involved. In contrast, these domains were dispensable for hormone-independent inhibition. Analysis of deletion mutants of ERα indicated that amino acids 179–215, containing the N-terminal zinc finger of the DNA-binding domain, were required for ligand-independent receptor action. Among different members of the nuclear receptor family, only unliganded ERα and ERβ reduced invasion. Calreticulin, a Ca2+-binding protein that could interact with amino acids 206–211 of ERα, reversed hormone-independent ERα inhibition of invasion. However, since calreticulin alone also inhibited invasion, we propose that this protein probably prevents ERα interaction with another unidentified invasion-regulating factor. The inhibitor role of the unliganded ER was also suggested in three ERα-positive cell lines, where ERα content was inversely correlated with cell migration. We conclude that ERα protects against cancer invasion in its unliganded form, probably by protein-protein interactions with the N-terminal zinc finger region, and after hormone binding by activation of specific gene transcription.

scholarly journals Pyk2 and FAK differentially regulate invadopodia formation and function in breast cancer cells

2017 ◽  
Vol 217 (1) ◽  
pp. 375-395 ◽  
Author(s):  
Alessandro Genna ◽  
Stefanie Lapetina ◽  
Nikola Lukic ◽  
Shams Twafra ◽  
Tomer Meirson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Focal Adhesion ◽  
Cell Invasion ◽  
Invasive Breast Cancer ◽  
Breast Cancer Cells ◽  
Tumor Cell Invasion ◽  
And Function

The nonreceptor tyrosine kinase Pyk2 is highly expressed in invasive breast cancer, but the mechanism by which it potentiates tumor cell invasiveness is unclear at present. Using high-throughput protein array screening and bioinformatic analysis, we identified cortactin as a novel substrate and interactor of proline-rich tyrosine kinase 2 (Pyk2). Pyk2 colocalizes with cortactin to invadopodia of invasive breast cancer cells, where it mediates epidermal growth factor–induced cortactin tyrosine phosphorylation both directly and indirectly via Src-mediated Abl-related gene (Arg) activation, leading to actin polymerization in invadopodia, extracellular matrix degradation, and tumor cell invasion. Both Pyk2 and the closely related focal adhesion kinase (FAK) regulate tumor cell invasion, albeit via distinct mechanisms. Although Pyk2 regulates tumor cell invasion by controlling invadopodium-mediated functions, FAK controls invasiveness of tumor cells by regulating focal adhesion–mediated motility. Collectively, our findings identify Pyk2 as a unique mediator of invadopodium formation and function and also provide a novel insight into the mechanisms by which Pyk2 mediates tumor cell invasion.

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