scholarly journals In Silico Discovery of Mitosis Regulation Networks Associated with Early Distant Metastases in Estrogen Receptor Positive Breast Cancers

2013 ◽  
Vol 12 ◽  
pp. CIN.S10329 ◽  
Author(s):  
Yuriy Gusev ◽  
Rebecca B. Riggins ◽  
Krithika Bhuvaneshwar ◽  
Robinder Gauba ◽  
Laura Sheahan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
In Silico ◽  
Expression Profiles ◽  
Metastatic Breast ◽  
Distant Metastases ◽  
Mitotic Checkpoint ◽  
Breast Cancers ◽  
Estrogen Receptor Positive

The aim of this study was to perform comparative analysis of multiple public datasets of gene expression in order to identify common genes as potential prognostic biomarkers. Additionally, the study sought to identify biological processes and pathways that are most significantly associated with early distant metastases (<5 years) in women with estrogen receptor-positive (ER+) breast tumors. Datasets from three published studies were selected for in silico analysis of gene expression profiles of ER+ breast cancer, using time to distant metastasis as the clinical endpoint. A subset of 44 differently expressed genes (DEGs) was found common to all three studies and characterized by mitotic checkpoint genes and pathways that regulate mitotic spindle and chromosome dynamics. DEG promoter regions were enriched with NFY binding sites. Analysis of miRNA target sites identified significant enrichment of miR-192, miR-193B, and miR-16–1 targets. Aberrant mitotic regulation could drive increased genomic instability leading to a progression towards an early onset metastatic phenotype. The relative importance of mitotic instability may reflect the clinical utility of mitotic poisons in metastatic breast cancer, including poisons such as the taxanes, epothilones, and vinca alkaloids.

scholarly journals Evaluating the effects of RAS and CK2 Inhibitors in ESR1 Mutated Breast Cancer

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Camilo Suescum ◽  
Harikrishna Nakshatri
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast ◽  
Ras Signaling ◽  
Breast Cancers ◽  
Metastatic Progression ◽  
Estrogen Receptor Positive ◽  
Signaling Inhibitors ◽  
Esr1 Mutation ◽  
Ck2 Inhibitors

Background and Hypothesis: Estrogen Receptor alpha (ESR1) is rarely mutated in primary breast cancers but is frequently mutated in metastasis that can appear after many years of anti-estrogen therapy. Mutations to ESR1 can result in estrogen-independent activity of ESR1 causing anti-estrogen to become ineffective. Previous work on this project has led to the hypothesis that RAS pathway activation in metastatic cancer cells as a result of ESR1 mutation leads to elevated CK2 activity which ultimately results in metastatic progression. Therefore, we hypothesize that the use of RAS signaling inhibitors or CK2 inhibitors have efficacy in blocking or reducing the metastatic progression of metastatic breast cancers with hyperactive RAS pathways. Experimental Design or Project Methods: The estrogen receptor positive, anti-estrogen sensitive breast cancer cell line MCF-7 and the same cell line genomically modified to replace wild type ESR1 to breast cancer metastasis enriched Y537S or D538G ESR1 mutation were used in this study. Cells were treated with various concentrations of the RAS pathway inhibitor Salirasib or CK2 inhibitor Silmitasertib and cell proliferation rates were measured using bromodeoxyuridine incorporation ELISA. Results: Thus far, the use of RAS signaling inhibitors or CK2 inhibitors have not shown efficacy in decreasing the proliferation rates of modified ESR1 MCF-7 cells. While there is a general trend of growth inhibition by these inhibitors at a higher concentration, there is no significant difference between the ESR1 mutant expressing cells and their respective controls.  Conclusion and Potential Impact: This study will establish the feasibility of using RAS signaling inhibitors or CK2 inhibitors in the treatment of metastatic estrogen receptor-positive breast cancer. Future studies testing the effects of these drugs either alone or in combination with the clinically used anti-estrogen Fulvestrant for not only primary tumor growth but also metastasis in clinically relevant in vivo models may ultimately lead to clinical translation.  Finally, demonstrating efficacy in these types of drugs may fuel the further refinement of drugs targeting these pathways to treat metastatic breast cancer.

scholarly journals Classification of Estrogen Receptor-Positive Breast Cancer Based on Immunogenomic Profiling and Validation at Single-Cell Resolution

2021 ◽  
Vol 9 ◽  
Author(s):  
Xianxiong Ma ◽  
Hengyu Chen ◽  
Ming Yang ◽  
Zunxiang Ke ◽  
Mengyi Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Single Cell ◽  
Expression Profiles ◽  
Immunosuppressive Agents ◽  
Mesenchymal Transition ◽  
Estrogen Receptor Positive ◽  
Genome Scale ◽  
Positive Breast Cancer

Background: The aim of this paper was to identify an immunotherapy-sensitive subtype for estrogen receptor-positive breast cancer (ER+ BC) patients by exploring the relationship between cancer genetic programs and antitumor immunity via multidimensional genome-scale analyses.Methods: Multidimensional ER+ BC high-throughput data (raw count data) including gene expression profiles, copy number variation (CNV) data, single-nucleotide polymorphism mutation data, and relevant clinical information were downloaded from The Cancer Genome Atlas to explore an immune subtype sensitive to immunotherapy using the Consensus Cluster Plus algorithm based on multidimensional genome-scale analyses. One ArrayExpress dataset and eight Gene Expression Omnibus (GEO) datasets (GEO-meta dataset) as well as the Molecular Taxonomy of Breast Cancer International Consortium dataset were used as validation sets to confirm the findings regarding the immune profiles, mutational features, and survival outcomes of the three identified immune subtypes. Moreover, the development trajectory of ER+ BC patients from the single-cell resolution level was also explored.Results: Through comprehensive bioinformatics analysis, three immune subtypes of ER+ BC (C1, C2, and C3, designated the immune suppressive, activation, and neutral subtypes, respectively) were identified. C2 was associated with up-regulated immune cell signatures and immune checkpoint genes. Additionally, five tumor-related pathways (transforming growth factor, epithelial–mesenchymal transition, extracellular matrix, interferon-γ, and WNT signaling) tended to be more activated in C2 than in C1 and C3. Moreover, C2 was associated with a lower tumor mutation burden, a decreased neoantigen load, and fewer CNVs. Drug sensitivity analysis further showed that C2 may be more sensitive to immunosuppressive agents.Conclusion: C2 (the immune activation subtype) may be sensitive to immunotherapy, which provides new insights into effective treatment approaches for ER+ BC.

scholarly journals JARID1A and IGF2R are concomitantly up-regulated in trastuzumab-treated human breast cancers.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Growth Factor ◽  
Expression Profiles ◽  
Regulation Of Gene Expression ◽  
Metastatic Breast ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Primary Tumors

Epigenetic regulation of gene expression is a mechanism by which signals transduced at the plasma membrane be can translated into differences in mRNA quantity and gene product at the protein level (1, 2). Trastuzumab is widely utilized for the treatment of adjuvant and metastatic breast cancer (3). We found, using analysis of public microarray and published multiplexed gene expression data (4, 5), that the histone lysine H3K4 demethylase JARID1A was among the genes whose expression was most significantly different when comparing the global gene expression profiles of trastuzumab-treated breast cancers and breast cancers not treated with trastuzumab. Expression of JARID1A in cancer cells has been associated with a drug-tolerant state with reduced drug sensitivity, dependent on insulin-like growth factor (IGF) signaling (6). Interestingly, we found that IGF2R was also among the genes whose expression was most significantly different transcriptome-wide when comparing the primary tumors of breast cancer patients treated with trastuzumab or not. These data clearly demonstrate up-regulation of a receptor for key growth factor signaling and together suggest that trastuzumab could be hard-wiring tumor cells for drug resistance.

scholarly journals Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women

2010 ◽  
Vol 28 (7) ◽  
pp. 1161-1167 ◽  
Author(s):  
Anita K. Dunbier ◽  
Helen Anderson ◽  
Zara Ghazoui ◽  
Elizabeth J. Folkerd ◽  
Roger A'Hern ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Postmenopausal Women ◽  
Multivariable Analysis ◽  
Independent Set ◽  
Breast Cancers ◽  
Plasma Estradiol ◽  
Er Positive ◽  
Positive Breast Cancer

Purpose To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)–positive breast cancers in postmenopausal women. Materials and Methods Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers. Results The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = −0.179; P = .05; and r = −0.389; P = .0005, respectively). Conclusion Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.

Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

2016 ◽  
Vol 34 (25) ◽  
pp. 2961-2968 ◽  
Author(s):  
Charlotte Fribbens ◽  
Ben O’Leary ◽  
Lucy Kilburn ◽  
Sarah Hrebien ◽  
Isaac Garcia-Murillas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Advanced Breast Cancer ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Phase Iii ◽  
Wild Type ◽  
Estrogen Receptor Positive ◽  
Esr1 Mutations ◽  
The Impact

Purpose ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor–positive advanced breast cancer. Materials and Methods In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. Results In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001). Conclusion ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.

Impact of 21-Gene Expression Assay on Staging Estrogen Receptor–Positive HER2-Negative Breast Cancer

2019 ◽  
Vol 19 (1) ◽  
pp. e261-e269 ◽  
Author(s):  
Andrea Breaux ◽  
Bradley Turner ◽  
Xiaoyong Wu ◽  
Shesh N. Rai ◽  
Elizabeth C. Riley ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Gene Expression Assay ◽  
Estrogen Receptor Positive

scholarly journals Practice-Changing Interventions in the Systemic Management of Breast Cancer

2020 ◽  
Vol 18 (7.5) ◽  
pp. 941-944
Author(s):  
William J. Gradishar
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Breast Cancer Subtype ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Targeted Agents ◽  
Her2 Positive ◽  
Nccn Guidelines ◽  
Estrogen Receptor Positive ◽  
Treatment Paradigm

Systemic treatment for metastatic breast cancer now incorporates many targeted agents and a plethora of combinations specific to the breast cancer subtype. New to the treatment paradigm are fam-trastuzumab deruxtecan-nxki, and tucatinib for HER2-positive disease; the PI3K inhibitor alpelisib in combination with fulvestrant for estrogen receptor–positive and PIK3CA-mutated tumors; PARP inhibitors for patients with germline BRCA1/2 mutations; and the anti–PD-L1 agent atezolizumab in combination with albumin-bound paclitaxel for triple-negative disease with PD-L1 mutations in tumors. In addition, for estrogen receptor–positive disease, the role of CDK4/6 inhibitors increased substantially during the past year, as overall survival results have emerged. These targeted agents are greatly improving patient outcomes, and thus have all been incorporated into the NCCN Guidelines for Breast Cancer.

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