TRIM39 is a poor prognostic factor for patients with estrogen receptor‐positive breast cancer and promotes cell cycle progression

2021 ◽  
Author(s):  
Takuya Ogura ◽  
Kotaro Azuma ◽  
Toshihiko Takeiwa ◽  
Junichiro Sato ◽  
Keiichi Kinowaki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Prognostic Factor ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Poor Prognostic Factor ◽  
Estrogen Receptor Positive ◽  
Positive Breast Cancer

scholarly journals Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer

2021 ◽  
Vol 22 (22) ◽  
pp. 12292
Author(s):  
Erin R. Scheidemann ◽  
Ayesha N. Shajahan-Haq
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cell Cycle Progression ◽  
Acquired Resistance ◽  
Alternative Methods ◽  
Cycle Progression ◽  
Estrogen Receptor Positive ◽  
New Treatment ◽  
Methods Of Treatment

Estrogen receptor-positive (ER+) breast cancer is the most common form of breast cancer. Antiestrogens were the first therapy aimed at treating this subtype, but resistance to these warranted the development of a new treatment option. CDK4/6 inhibitors address this problem by halting cell cycle progression in ER+ cells, and have proven to be successful in the clinic. Unfortunately, both intrinsic and acquired resistance to CDK4/6 inhibitors are common. Numerous mechanisms of how resistance occurs have been identified to date, including the activation of prominent growth signaling pathways, the loss of tumor-suppressive genes, and noncanonical cell cycle function. Many of these have been successfully targeted and demonstrate the ability to overcome resistance to CDK4/6 inhibitors in preclinical and clinical trials. Future studies should focus on the development of biomarkers so that patients likely to be resistant to CDK4/6 inhibition can initially be given alternative methods of treatment.

scholarly journals Expression and Clinical Significance of Origin Recognition Complex Family in Breast Cancer

2021 ◽  
Author(s):  
shaohua chen ◽  
Ziyao Jin ◽  
Linfeng Xin ◽  
Lv Lv ◽  
Xuemei Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Origin Recognition Complex ◽  
Diagnostic Value ◽  
Breast Cancer Patients ◽  
Cycle Progression ◽  
Poor Prognostic Factor ◽  
Node Metastasis ◽  
Cancer Tissues

Abstract BackgroundThe aim of this study is to investigate the potential clinical and prognostic value, role and driving molecular mechanisms of the origin recognition complex family in breast cancer.Resultsata from Oncomine, TCGA, GEO and ULCAN showed that ORC1L and ORC6L were highly expressed in breast cancer tissues, while the expression of ORC5L was inconsistent and there was no significant difference in the expression of ORC2L, ORC3L and ORC4L. High expression of ORC1L and ORC6L were mainly Her2 overexpressed subtype, and their expression were negatively correlated with patient age and positively correlated with tumor size, but not with lymph node metastasis, distant metastasis, or tumor stage. Expression of ORC5L was also negatively correlated with age and positively correlated with lymph node metastasis, but not with breast cancer molecular subtype and tumor size. Expression of ORC1L and ORC5L had high diagnostic value, and ORC6L had the highest diagnostic value in breast cancer. ORC6L was an independent poor prognostic factor for overall survival of breast cancer patients. It was involved in cell cycle progression, cell senescence, epigenetic regulation and other biological functions, and may regulate signaling pathways such as NF-KB, TP53 and WNT in breast cancer. We also found that the expression of ORC6L was related to the increased infiltration of Th1/2 cell and Treg cell, and decreased infiltration of Mast cell and NK cell.ConclusionsORC1L and ORC6L are highly expressed in breast cancer tissues, of which ORC6L has high diagnostic value and is an independent poor prognostic factor for overall survival of breast cancer patients. ORC6L may be involved in the occurrence and progression of breast cancer by regulating cell cycle progression, promoting the activation of cancer signaling pathways, and influencing tumor immune cells infiltration.

scholarly journals SAT-LB135 A Novel Cytoplasmic Membrane Estrogen-Mediated Biogenic Signaling Pathway

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Richard G Pestell
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cyclin D1 ◽  
Signaling Pathway ◽  
Cell Cycle Progression ◽  
Cytoplasmic Membrane ◽  
Cycle Progression ◽  
17Β Estradiol ◽  
Localized Form

Abstract The estrogen receptor α (ERα) is known to convey both genomic and extra-genomic activities. The extra-nuclear estrogen signaling pathway is thought to involve a membrane-associated estrogen receptor (ERα), which activates PI3-kinase and Akt signaling. Maximal activation of Akt requires S473 phosphorylation. The essential G1-cyclin, CCND1, is a collaborative nuclear oncogene that is frequently overexpressed in cancer. D-type cyclins bind and activate CDK4/6, contributing to G1-S cell-cycle progression. Herein, cyclin D1 was shown to be located in the cytoplasmic membrane of patients with inflammatory breast cancer, human diploid fibroblasts and cancer cell lines (breast, prostate). The extra-nuclear vs. nuclear E2-induced signaling pathways can be distinguished using 17β-estradiol linked to a dendrimer conjugate (EDC), which excludes estradiol from the nucleus. In contrast with the nuclear-localized form of cyclin D1 (cyclin D1NL), the cytoplasmic membrane-localized form of cyclin D1 (cyclin D1CML) was sufficient to induce phosphorylation of the serine threonine kinase Akt (Ser473) and augmented extra-nuclear localized 17β-estradiol dendrimer conjugate (EDC)-mediated phosphorylation of Akt (Ser473). Cyclin D1CML was sufficient to induce G1-S cell-cycle progression, cellular proliferation, colony formation. In contrast with cyclin D1NL, the cyclin D1CML induced transwell migration and the velocity of cellular migration. Together these studies suggest distinct subcellular compartments of cell cycle proteins may convey distinct functions. The major adjuvant therapy for the ~70% of ERα expressing human breast cancer involves anti-estrogen therapy and the ERα/PI3K/Akt complex pathway is hyperactivated in aggressive breast tumors. The non-genomic actions of E2/ERα, mediated via cyclin D1CML may provide an important additional target. References. 1. 2. Casimiro MC et al Mol Endocrinol. 2013;27(9):1415-28. Di Sante, G, Expert Rev Anticancer Ther. 2019 Jun 20:1-19.

scholarly journals Cell Cycle Progression Stimulated by Tamoxifen-Bound Estrogen Receptor-α and Promoter-Specific Effects in Breast Cancer Cells Deficient in N-CoR and SMRT

2005 ◽  
Vol 19 (6) ◽  
pp. 1543-1554 ◽  
Author(s):  
Erika Krasnickas Keeton ◽  
Myles Brown
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cell Cycle Progression ◽  
Hormone Receptors ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Cycle Progression

Abstract Estrogen receptor α (ERα) mediates the effects of estrogens in breast cancer development and growth via transcriptional regulation of target genes. Tamoxifen can antagonize ERα activity and has been used in breast cancer therapy. Tamoxifen-bound ERα associates with nuclear receptor corepressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) at certain target genes. Here we show the effects of reducing N-CoR and SMRT levels on the actions of estrogen and tamoxifen in breast cancer cells. Silencing both corepressors led to tamoxifen-stimulated cell cycle progression without activation of the ERα target genes c-myc, cyclin D1, or stromal cell-derived factor 1, which play a role in estrogen-induced proliferation. By contrast, expression of X-box binding protein 1 was markedly elevated in tamoxifen-treated cells in which N-CoR and SMRT had been silenced. The gain in cell cycle entry seen with tamoxifen when N-CoR and SMRT were silenced was dependent on ERα and not observed upon treatment with estradiol or epidermal growth factor. These results suggest that N-CoR and SMRT play an active role in preventing tamoxifen from stimulating proliferation in breast cancer cells through repression of a subset of target genes involved in ERα function and cell proliferation.

scholarly journals Interaction of the Double-Strand Break Repair Kinase DNA-PK and Estrogen Receptor-α

2010 ◽  
Vol 21 (9) ◽  
pp. 1620-1628 ◽  
Author(s):  
Senad Medunjanin ◽  
Sönke Weinert ◽  
Alexander Schmeisser ◽  
Doris Mayer ◽  
Ruediger C. Braun-Dullaeus
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cell Cycle Progression ◽  
Hormone Receptors ◽  
Cancer Cell Line ◽  
Strand Break ◽  
Estrogen Receptor Α ◽  
Steroid Hormone Receptors ◽  
Cycle Progression

Estrogens are suggested to play a role in the development and progression of proliferative diseases such as breast cancer. Like other steroid hormone receptors, the estrogen receptor-α (ERα) is a substrate of protein kinases, and phosphorylation has profound effects on its function and activity. Given the importance of DNA-dependent protein kinase (DNA-PK) for DNA repair, cell cycle progression, and survival, we hypothesized that it modulates ERα signaling. Here we show that, upon estrogen stimulation, DNA-PK forms a complex with ERα in a breast cancer cell line (MELN). DNA-PK phosphorylates ERα at Ser-118. Phosphorylation resulted in stabilization of ERα protein as inhibition of DNA-PK resulted in its proteasomal degradation. Activation of DNA-PK by double-strand breaks or its inhibition by siRNA technology demonstrated that estrogen-induced ERα activation and cell cycle progression is, at least, partially dependent on DNA-PK.

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