Effect of depletion of CDK4 on gene expression of MCF-7 breast cance cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE261797 | GEO | 2024/09/17
REPOSITORIES: GEO
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Project description:Inhibitors for cyclin-dependent kinase (CDK) 4 and CDK6 have been established as effective therapeutic options for hormone receptor (HR)-positive, HER2-negative advanced breast cancer. Although the CDK4/6 inhibitors mainly target the cyclin D-CDK4/6-retinoblastoma tumor suppressor protein (RB) axis, little is known about clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we have focused on other CDK4/6 targets, SMAD proteins. We showed that a CDK4/6 inhibitor Palbociclib and Activin-SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal-type breast cancer cell line T47D. Mechanistically, Palbociclib enhanced SMAD2 binding to the genome through inhibiting linker phosphorylation of the SMAD2 protein by CDK4/6. Comparison of the SMAD2 ChIP-seq data of T47D with those of a triple-negative breast cancer cell line Hs578T indicated that Palbociclib augments different SMAD2-mediated program defined based on types of cells, and enhances SMAD2 binding to the target regions on the genome without affecting its binding pattern. Collectively, the CDK4/6 inhibitor facilitates the cytostatic effects of Activin-SMAD2, while it also enhances its tumor promoting effects depending on types of breast cancer.
2018-10-23 | GSE117496 | GEO
Project description:Inhibitors for cyclin-dependent kinase (CDK) 4 and CDK6 have been established as effective therapeutic options for hormone receptor (HR)-positive, HER2-negative advanced breast cancer. Although the CDK4/6 inhibitors mainly target the cyclin D-CDK4/6-retinoblastoma tumor suppressor protein (RB) axis, little is known about clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we have focused on other CDK4/6 targets, SMAD proteins. We showed that a CDK4/6 inhibitor Palbociclib and Activin-SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal-type breast cancer cell line T47D. Mechanistically, Palbociclib enhanced SMAD2 binding to the genome through inhibiting linker phosphorylation of the SMAD2 protein by CDK4/6. Comparison of the SMAD2 ChIP-seq data of T47D with those of a triple-negative breast cancer cell line Hs578T indicated that Palbociclib augments different SMAD2-mediated program defined based on types of cells, and enhances SMAD2 binding to the target regions on the genome without affecting its binding pattern. Collectively, the CDK4/6 inhibitor facilitates the cytostatic effects of Activin-SMAD2, while it also enhances its tumor promoting effects depending on types of breast cancer.
2018-10-23 | GSE117495 | GEO
Project description:Background: Estrogen receptor-positive (ER+) breast cancers represent approximately two-thirds of all breast cancers and have a sustained risk of late disease recurrence. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown significant efficacy in ER+ breast cancer. However, their effects are still limited by drug resistance. In this study, we aim to explore the role of long noncoding RNA TROJAN in ER+ breast cancer. Methods: The expression level of TROJAN in breast cancer tissue and cell lines was determined by quantitative real-time PCR. In vitro and in vivo assays as well as patient derived organoids were preformed to explore the phenotype of TROJAN in ER+ breast cancer. The TROJAN-NKRF-CDK2 axis were screened and validated by RNA pull-down, mass spectrometry, RNA immunoprecipitation, microarray, dual-luciferase reporter and chromatin immunoprecipitation assays. Results: Herein, we showed that TROJAN was highly expressed in ER+ breast cancer. TROJAN promoted cell proliferation and resistance to a CDK4/6 inhibitor and was associated with poor survival in ER+ breast cancer. TROJAN can bind to NKRF and inhibit its interaction with RELA, upregulating the expression of CDK2. The inhibition of TROJAN abolished the activity of CDK2, reversing the resistance to CDK4/6 inhibitor. A TROJAN antisense oligonucleotide sensitized breast cancer cells and organoids to the CDK4/6 inhibitor palbociclib both in vitro and in vivo. Conclusions: TROJAN promotes ER+ breast cancer proliferation and is a potential target for reversing CDK4/6 inhibitor resistance.
2020-04-18 | GSE148858 | GEO
Project description:Cyclin D-CDK4/6 are the first CDK complexes to be activated in G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (Palbociclib) was recently approved by the FDA to treat advanced ER+ breast tumors. Unfortunately, reliable predictive tools are lacking to identify potentially responsive or insensitive tumors. We have shown that the activating T172 phosphorylation of CDK4 is the central rate-limiting event that initiates the cell cycle decision and signals the presence of active CDK4. Here, we found that, in breast cancer cell lines, the CDK4 T172 phosphorylation best correlates with the sensitivity to PD0332991. Moreover, the modification profile of CDK4 differs among breast tumors and it associates with their subtypes and risk. A gene expression signature faithfully predicted CDK4 modification profiles in tumors and cell lines. This surrogate biomarker identifies tumors that are unlikely to respond to CDK4/6 inhibitors and could allow extending the indication of the drug to HER-2 positive and some basal-like tumors. Predictive tools to identify breast cancer patients sensitive to Pfizer's new drug targeting CDK4/6 are lacking. We correlated the sensitivity of breast cancer cell lines to the drug to their post-translational modification profile of CDK4 revealed by 2D SDS/poly-acrylamide gel electrophoresis followed by CDK4 immuno-detection and their gene expression profiles. we revealed that breast tumors display similar CDK4 post-translational modification profiles as cell lines and that a gene expression profile can be used to predict the CDK4 post-translational modification profile of a tumor or cell line and thereby its sensitivity to CDK4 inhibitor
2017-01-01 | GSE87007 | GEO
Project description:Cyclin D-CDK4/6 are the first CDK complexes to be activated in G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (Palbociclib) was recently approved by the FDA to treat advanced ER+ breast tumors. Unfortunately, reliable predictive tools are lacking to identify potentially responsive or insensitive tumors. We have shown that the activating T172 phosphorylation of CDK4 is the central rate-limiting event that initiates the cell cycle decision and signals the presence of active CDK4. Here, we found that, in breast cancer cell lines, the CDK4 T172 phosphorylation best correlates with the sensitivity to PD0332991. Moreover, the modification profile of CDK4 differs among breast tumors and it associates with their subtypes and risk. A gene expression signature faithfully predicted CDK4 modification profiles in tumors and cell lines. This surrogate biomarker identifies tumors that are unlikely to respond to CDK4/6 inhibitors and could allow extending the indication of the drug to HER-2 positive and some basal-like tumors. Predictive tools to identify breast cancer patients sensitive to Pfizer's new drug targeting CDK4/6 are lacking. We correlated the sensitivity of breast cancer cell lines to the drug to their post-translational modification profile of CDK4 revealed by 2D SDS/poly-acrylamide gel electrophoresis followed by CDK4 immuno-detection and their gene expression profiles. we revealed that breast tumors display similar CDK4 post-translational modification profiles as cell lines and that a gene expression profile can be used to predict the CDK4 post-translational modification profile of a tumor or cell line and thereby its sensitivity to CDK4 inhibitor
2017-01-01 | GSE87006 | GEO
Project description:Cyclin Dependent Kinase 4/6 inhibitors induce transcription in breast tumors via FOXA1 chromatin binding. The use of Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i) induce transcription in breast tumors. The control mechanism of such genomic changes and their physiological relevance are not elucidated yet. Now, we identified chromatin activation of tumors treated with CDK4/6i. These chromatin changes induce an increase of HER2 expression and signaling. Mechanically, our study demonstrates that FOXA1 is a new substrate of CDK4 and that its phosphorylation limits the binding of FOXA1 to conventional chromatin regions. Moreover, when patients are treated with CDK4/6i, a dephosphorylated FOXA1 binds to additional chromatin regions. By doing so, FOXA1 leads to an increase of HER2 expression and of the activation of HER2-MEK-ERK pathway in breast cancer patients. Accordingly, we might envision a clinical benefit of adding antiHER2 therapy to delay development of resistance and therefore, to prolong PFS in patients yet receiving CDK4/6i.
2023-09-01 | GSE231544 | GEO
Project description:Resistance to aromatase inhibitor (AI) treatment and combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) are crucial clinical challenges in treating estrogen receptor-positive (ER+) breast cancer. Understanding the resistance mechanisms and identifying reliable predictive biomarkers and novel treatment combinations to overcome resistance are urgently needed. Herein, we show that upregulation of CDK6, p-CDK2, and/or cyclin E1 is associated with adaptation and resistance to AI-monotherapy and combined CDK4/6i and ET in ER+ advanced breast cancer. Importantly, co-targeting CDK2 and CDK4/6 with ET synergistically impairs cellular growth, induces cell cycle arrest and apoptosis, and delays progression in AI-resistant and combined CDK4/6i and fulvestrant-resistant cell models and in an AI-resistant autocrine breast tumor in a postmenopausal xenograft model. Analysis of CDK6, p-CDK2, and/or cyclin E1 expression as a combined biomarker in metastatic lesions of ER+ advanced breast cancer patients treated with AI-monotherapy or combined CDK4/6i and ET revealed a correlation between high biomarker expression and shorter progression-free survival (PFS), and the biomarker combination was an independent prognostic factor in both patients cohorts. Our study supports the clinical development of therapeutic strategies co-targeting ER, CDK4/6 and CDK2 following progression on AI-monotherapy or combined CDK4/6i and ET to improve survival of patients exhibiting high tumor levels of CDK6, p-CDK2, and/or cyclin E1.
2022-08-05 | GSE210399 | GEO
Project description:Cyclin dependent kinase 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycle entry, at least in part through phosphorylation of the retinoblastoma tumor suppressor protein (Rb). The CDK4/6-cyclin D-Rb pathway is commonly deregulated in human cancer, often through CDK4/6 or D-type cyclin overexpression, or inactivation of the CDK4/6 antagonist p16/CDKN2A. Importantly, a substantial fraction of cancers depend on continuous CDK4/6-cyclin D kinase activity and are sensitive to CDK4/6-specific inhibitors. Here, we investigate critical CDK4/6-cyclin D functions that may determine the sensitivity to CDK4/6 inhibitors, making use of the essential roles of CDK4/6 (CDK-4) and cyclin D (CYD-1) in the nematode C. elegans. In an unbiased screen, we found that simultaneous loss of C. elegans Rb (lin-35) and down-regulation of the APC/C substrate specificity factor FZR1/Cdh1 completely overcomes CDK-4/CYD-1 requirement. Furthermore, CDK-4/CYD-1 phosphorylates specific residues in the LIN-35 Rb spacer domain and FZR-1 N-terminus that correspond to inactivating phosphorylations of the human homologs. Thus, CDK-4/CYD-1 appears to promote cell cycle entry by antagonizing not only transcriptional repression by LIN-35 Rb but also protein degradation by APC/CFZR-1. Simultaneous knockdown of Rb and FZR1 in human breast cancer cells synergistically overcomes arrest by the CDK4/6-specific inhibitor PD 00332991. These results reveal APC/CFZR1 as a putative CDK4/6-Cyclin D target and important contributing factor in the response to CDK4/6-inhibitor treatment.
2016-07-05 | PXD001501 | Pride
Project description:CDK4/6 inhibition is the standard of care for estrogen receptor positive (ER+) breast cancer, although cytostasis is frequently observed, and new treatment strategies that enhance efficacy are required. We performed a genome-wide CRISPR screen to identify genetic determinants of CDK4/6 inhibitors sensitivity. Multiple genes involved in oxidative stress and ferroptosis modulated palbociclib sensitivity. Depletion or inhibition of GPX4 increased sensitivity to palbociclib in ER+ breast cancer models, and sensitised triple negative breast cancer models to palbociclib, with GPX4 null xenografts being highly sensitive to palbociclib. Palbociclib induced oxidative stress and disordered lipid metabolism with lipid peroxidation, leading to a ferroptosis-sensitive state. Lipid peroxidation relied on a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 inhibition creates vulnerability to ferroptosis that could be exploited through combination with GPX4 inhibitors, enhancing sensitivity to CDK4/6 inhibition in breast cancer.
2023-06-20 | PXD043133 | Pride
Project description:Purpose: Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER) positive (ER+) breast cancer (BC). Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine resistant ER+ BC models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ BC. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ BC remain elusive. Herein, we sought to unravel these mechanisms. Experimental Design: We conducted multi-omic analyses in ER+ BC models in vitro and in vivo including models with different genetic backgrounds. We also performed genome wide CRISPR knock-out library screens to identify potential therapeutic vulnerabilities in CDK4/6i resistance models. Results: We found that the on-target anti-tumor effects of CDK7 inhibition in ER+ BC are in part p53 dependent, involve cell-cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ETs and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118, however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Lastly, genome wide CRISPR/Cas9 screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i resistant models. Conclusions: Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ BC. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors for sensitivity to CDK7 inhibitor-based treatments.
2024-02-12 | GSE230362 | GEO