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Microarray gene expression data from MCF-7 and MPiFR cells

ABSTRACT: The PI3K inhibitor (PI3Ki) alpelisib in combination with fulvestrant is currently FDA approved for the treatment of advanced ER+ breast cancer following progression on endocrine therapy. It is unclear which treatment strategy is beneficial following progression on the combination of PI3Ki and fulvestrant, and therefore, identification of novel therapeutic targets is needed. We used microarrays to detail the global programme of gene expression in cells resistant to the combination of PI3Ki and fulvestrant (MPiFR). The parental sensitive cell line, MCF-7, was used for comparison. The gene expression analysis revealed a significant number of genes altered in the MPiFR cells vs. MCF-7 cells. We found a significant upregulation of cell cycle-related genes, particularly CDK6, CDK2, and cyclin E1 and E2 in MPiFR vs. MCF-7 cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210400 | GEO | 2022/08/05

REPOSITORIES: GEO

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Microarray gene expression data from MCF-7 and LetR cells

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

High CDK6 protects cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant in estrogen receptor-positive metastatic breast cancer

Project description:Purpose: Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a major clinical problem. Recently, the CDK4/6 inhibitor palbociclib combined with letrozole was approved for treatment of ER+ advanced breast cancer, and other CDK4/6 inhibitors are being investigated in combination with different endocrine treatments. However, the role of CDK4/6 in endocrine resistance and their potential as predictive biomarkers of endocrine treatment response remains undefined. Experimental Design: We investigated the specific role of increased CDK6 expression in fulvestrant-resistant cells by gene knockdown and treatment with palbociclib, and evaluated the effect in cell proliferation, apoptosis and kinase activity. Furthermore, we evaluated CDK6 expression in metastatic samples from breast cancer patients treated or not with fulvestrant. Results: We found increased expression of CDK6 in two fulvestrant-resistant cell models vs. sensitive cells. Reduction of CDK6 expression impaired fulvestrant-resistant cell growth and induced apoptosis by reducing p70 ribosomal S6 kinase 2 activity. Treatment with palbociclib re-sensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma phosphorylation. High CDK6 levels in metastatic samples from breast cancer patients treated with fulvestrant (N=45) correlated significantly with shorter progression-free survival (PFS) (p=0.0006), while no association was observed in patients receiving other endocrine treatments (N=41, p=0.874). Conclusions: Our results indicate that upregulation of CDK6 may be an important mechanism in overcoming fulvestrant-mediated growth inhibition in breast cancer cells. Patients with advanced ER+ breast cancer exhibiting high CDK6 expression in the metastatic lesions show shorter PFS upon fulvestrant treatment and thus may benefit from the addition of CDK4/6 inhibitors in their therapeutic regimens.

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Phosphoproteomics of BYL719 (alpelisib)-Resistant T47D Human Breast Cancer Cell Line

Project description:The PI3Kalpha-specific inhibitor Alpelisib (BYL719) has been approved for the treatment of metastatic ER+/HER2- breast cancer patients in combination with Fulvestrant. After initial response, patients develop drug resistance and disease relapses. In order to identify signalling pathways contributing to the acquired resistance to BYL719 in breast cancer, we generated BYL719-resistant T47D cells and used them together with the parental cells to perform label-free quantitative phosphoproteomics.

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The major pre- and post-menopausal estrogens play opposing roles in obesity driven mammary inflammation and breast cancer development

Project description:Purpose: The goals of this study : Estrone(E1) vs Estradial (E2) in breast cancer inflammatory signaling and breast cancer progression. Is HSD17B14 that convert E2 to E1 the oncogene.

2020-06-21 | GSE132913 | GEO

Copy number analysis of OVCAR-3 and CDK2 resistant sublines

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Fulvestrant withdrawal from fulvestrant-resistant MCF-7/FR cells

Project description:Fulvestrant withdrawal from fulvestrant-resistant MCF-7/FR cells

| PRJNA497213 | ENA

Copy number analysis of OVCAR-3 and CDK2 resistant sublines

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2013-09-01 | E-GEOD-48920 | biostudies-arrayexpress

Gene expression analysis of OVCAR-3 and CDK2 resistant sublines

Project description:Cyclin E1 (CCNE1) is amplified in various tumor types including high-grade serous ovarian cancer where it is associated with poor clinical outcome. We have demonstrate that suppression of the Cyclin E1 partner kinase, CDK2, induces apoptosis in a CCNE1 amplicon-dependent manner. Little is known of mechanisms of resistance to CDK inhibitors. We therefore generated OVCAR-3 sublines with reduced sensitivity to CDK2 inhibitors and profiled by gene expression microarrays. Arrayed samples included parental OVCAR-3 cells (n = 4 replicates) and five independently derived sublines resistant to PHA-533533 (OVCAR3-533533-R1, -R3, -R5, -R6, -R7). The resistant cell lines were arrayed after drug selection (P5) and after continued passage in the absence of inhibitor (P10+).

2013-09-01 | E-GEOD-48919 | biostudies-arrayexpress

ChIP-Seq of ERalpha and RNA polymerase II defines genes differentially responding to ligands

Project description:We used ChIP-Seq to map ERalpha binding sites and to profile changes in RNA polymerase II (RNAPII) occupancy in MCF-7 cells in response to estradiol (E2), tamoxifen or fulvestrant. We identified 10,205 high confidence ERalpha binding sites in response to E2 of which 68% contained an estrogen response element (ERE) and only 7% contained a FOXA1 motif. Remarkably, 596 genes already change significantly in RNAPII occupancy (59% up and 41% down) following one hour of E2 exposure. Although pausing of RNA polymerase II occurs frequently in MCF-7 cells (17%) it is only observed on a minority of E2-regulated genes (4%). Tamoxifen and fulvestrant partially reduce ERalpha DNA binding and prevent RNAPII loading on the promoter and coding body on E2-upregulated genes. Both antagonists act differently on E2-downregulated genes. Tamoxifen acts as an agonist, also downregulating these genes while fulvestrant antagonizes E2 induced repression and often increases RNAPII occupancy. Furthermore our data identified genes preferentially regulated by tamoxifen but not by E2 or fulvestrant. Thus, antagonist loaded ERalpha acts mechanistically different on E2-activated and E2-repressed genes.

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