Revisiting the role of MCL1 in tumorigenesis of solid cancer: gene expression correlates with antiproliferative phenotype in breast cancer cells and its functional regulatory variants are associated with reduced cancer susceptibility

AbstractChromatin modifier metastasis-associated protein 1 (MTA1), closely correlated with the development and progression in breast cancer, has a vital role in multiple cellular processes, including gene expression and cell homeostasis. Although MTA1 is a stress-responsive gene, its role in genotoxic adaptation remains unexplored. The current study sought to investigate the role of MTA1 and its O-GlcNAc modification in breast cancer cells genotoxic adaptation by using quantitative proteomics, ChIP-seq, transcriptome analysis, loss-and gain-of-functions experiments. We demonstrate that O-GlcNAc modification promotes MTA1 to interact with chromatin and regulates target gene expression, contributing to breast cancer cell genotoxic adaptation. MTA1 is modified with O-GlcNAc residues at serine 237/241/246 in adriamycin adaptive breast cancer cells and that modification improves the genome-wide interactions of MTA1 with gene promotor regions by enhancing its association with nucleosome remodeling and histone deacetylation (NuRD) complex. Further, O-GlcNAc-modulated MTA1 chromatin-binding influences the specific transcriptional regulation of genes involved in the adaptation of breast cancer cells to genotoxic stress. Our findings reveal a previously unrecognized role of O-GlcNAc MTA1 in transcriptional regulation and suggest that O-GlcNAc modification is a promising therapeutic target to overcome chemoresistance in breast cancers.

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Role of Nuclear Matrix in Estrogen Regulated Gene Expression in Human Breast Cancer Cells

10.21236/ada382697 ◽

1999 ◽

Author(s):

Laurel T. Holth

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Cells ◽

Nuclear Matrix ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Regulated Gene Expression

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Role of specificity protein transcription factors in estrogen-induced gene expression in MCF-7 breast cancer cells

Journal of Molecular Endocrinology ◽

10.1677/jme-07-0043 ◽

2007 ◽

Vol 39 (4) ◽

pp. 289-304 ◽

Cited By ~ 14

Author(s):

Shaheen Khan ◽

Fei Wu ◽

Shengxi Liu ◽

Qian Wu ◽

Stephen Safe

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Retinoic Acid Receptor ◽

Estrogen Receptor Α ◽

Mrna Levels ◽

Aspartate Transcarbamylase ◽

Mcf 7

AbstractDeletion analysis of several 17β-estradiol (E2)-responsive genes have identified GC-rich sites that are associated with hormone-induced transactivation in MCF-7 breast cancer cells. However, the role of individual specificity proteins (Sps) in mediating hormone-induced gene expression has not been unequivocally determined. In transient transfection studies using E2-responsive GC-rich promoters from the E2F1, carbamoylphosphate synthetase/aspartate transcarbamylase/dihydroorotase (CAD), and retinoic acid receptor α (RARα) genes, RNA interference using small inhibitory RNAs for Sp1 (iSp1), Sp3 (iSp3), and Sp4 (iSp4) decreased both basal and E2-induced transactivation. The contributions of individual Sp proteins to basal and E2-induced activity were promoter dependent. iSp1, iSp3, and iSp4 also significantly inhibited hormonal induction of E2F1, CAD, and RARα mRNA levels; however, the enhanced inhibitory effects of the latter two small inhibitory RNAs suggest that Sp3 and Sp4 play a major role in estrogen receptor α/Sp-mediated gene expression in MCF-7 cells.

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Genetic and epigenetic regulation of AHR gene expression in MCF-7 breast cancer cells: Role of the proximal promoter GC-rich region

Biochemical Pharmacology ◽

10.1016/j.bcp.2012.06.013 ◽

2012 ◽

Vol 84 (5) ◽

pp. 722-735 ◽

Cited By ~ 21

Author(s):

Neal A. Englert ◽

Robert J. Turesky ◽

Weiguo Han ◽

Erin E. Bessette ◽

Simon D. Spivack ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Cells ◽

Epigenetic Regulation ◽

Breast Cancer Cells ◽

Proximal Promoter ◽

Rich Region ◽

Ahr Gene ◽

Mcf 7

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Novel role of pyruvate dehydrogenase PDH ーregulation of histone acetylation and gene expression in breast cancer cells

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.94.0_2-p2-lb49 ◽

2021 ◽

Vol 94 (0) ◽

pp. 2-P2-LB49

Author(s):

Nakayama Koh

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Histone Acetylation ◽

Cancer Cells ◽

Pyruvate Dehydrogenase ◽

Breast Cancer Cells

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Hormonal Therapy Resistance and Breast Cancer: Involvement of Adipocytes and Leptin

Nutrients ◽

10.3390/nu11122839 ◽

2019 ◽

Vol 11 (12) ◽

pp. 2839 ◽

Cited By ~ 2

Author(s):

Laetitia Delort ◽

Lauriane Bougaret ◽

Juliette Cholet ◽

Marion Vermerie ◽

Hermine Billard ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Hormonal Therapy ◽

Breast Cancer Cells ◽

Hormonal Therapies ◽

The Impact

Obesity, a recognized risk factor for breast cancer in postmenopausal women, is associated with higher mortality rates regardless of menopausal status, which could in part be explained by therapeutic escape. Indeed, adipose microenvironment has been described to influence the efficiency of chemo- and hormonal therapies. Residual cancer stem cells could also have a key role in this process. To understand the mechanisms involved in the reduced efficacy of hormonal therapy on breast cancer cells in the presence of adipose secretome, human adipose stem cells (hMAD cell line) differentiated into mature adipocytes were co-cultured with mammary breast cancer cells and treated with hormonal therapies (tamoxifen, fulvestrant). Proliferation and apoptosis were measured (fluorescence test, impedancemetry, cytometry) and the gene expression profile was evaluated. Cancer stem cells were isolated from mammospheres made from MCF-7. The impact of chemo- and hormonal therapies and leptin was evaluated in this population. hMAD-differentiated mature adipocytes and their secretions were able to increase mammary cancer cell proliferation and to suppress the antiproliferative effect of tamoxifen, confirming previous data and validating our model. Apoptosis and cell cycle did not seem to be involved in this process. The evaluation of gene expression profiles suggested that STAT3 could be a possible target. On the contrary, leptin did not seem to be involved. The study of isolated cancer stem cells revealed that their proliferation was stimulated in the presence of anticancer therapies (tamoxifen, fulvestrant, doxorubicine) and leptin. Our study confirmed the role of adipocytes and their secretome, but above all, the role of communication between adipose and cancer cells in interfering with the efficiency of hormonal therapy. Among the pathophysiological mechanisms involved, leptin does not seem to interfere with the estrogenic pathway but seems to promote the proliferation of cancer stem cells.

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ESM-1 Overexpression is Involved in Increased Tumorigenesis of Radiotherapy-Resistant Breast Cancer Cells

Cancers ◽

10.3390/cancers12061363 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1363 ◽

Cited By ~ 2

Author(s):

Hana Jin ◽

Trojan Rugira ◽

Young Shin Ko ◽

Sang Won Park ◽

Seung Pil Yun ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Critical Role ◽

Migration And Invasion ◽

Expression Array ◽

4T1 Cells

The key barrier to the effectiveness of radiotherapy remains the radioresistance of breast cancer cells, resulting in increased tumor recurrence and metastasis. Thus, in this study, we aimed to clarify the difference between radiotherapy-resistant (RT-R) breast cancer (BC) and BC, and accordingly, analyzed gene expression levels between radiotherapy-resistant (RT-R) MDA-MB-231 cells and MDA-MB-231 cells. Gene expression array showed that ESM-1 was the most upregulated in RT-R-MDA-MB-231 cells compared to MDA-MB-231 cells. Then, we aimed to investigate the role of ESM-1 in the increased tumorigenesis of RT-R-BC cells. RT-R-MDA-MB-231, which showed an increased expression level of ESM1, exhibited significantly enhanced proliferation, colony forming ability, migration, and invasion compared to MDA-MB-231 cells, and ESM-1 knockdown effectively reversed these effects. In addition, compared to MDA-MB-231 cells, RT-R-MDA-MB-231 cells displayed improved adhesion to endothelial cells (ECs) due to the induction of adhesion molecules and increased MMP-9 activity and VEGF-A production, which were decreased by ESM-1 knockdown. Moreover, the expression of HIF-1α and activation of NF-κB and STAT-3 were increased in RT-R-MDA-MB-231 cells compared to MDA-MB-231 cells, and these effects were abolished by the knockdown of ESM-1. Finally, we confirmed the role of ESM-1 in tumorigenesis in an in vivo mouse model. Tumor volume, lung metastasis, and tumorigenic molecules (VEGF-A, HIF-1α, MMP-9, ICAM-1, VCAM-1, and phospho-NF-κB and phospho-STAT-3) were significantly induced in mice injected with ESM-1-overexpressing 4T1 cells and greatly enhanced in those injected with ESM-1-overexpressing RT-R-4T1 cells. Taken together, these results suggest for the first time that ESM-1 plays a critical role in tumorigenesis of breast cancer cells, especially RT-R-breast cancer cells, through the induction of cell proliferation and invasion.

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