scholarly journals Cyclin E1 and cyclin E2 in ER+ breast cancer: prospects as biomarkers and therapeutic targets

2020 ◽  
Vol 27 (5) ◽  
pp. R93-R112 ◽  
Author(s):  
H H Milioli ◽  
S Alexandrou ◽  
E Lim ◽  
C E Caldon
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Standard Of Care ◽  
Cdk Inhibitors ◽  
Cyclin E1 ◽  
Phase Ii Clinical Trials ◽  
Cdk2 Activity ◽  
Cyclin E2 ◽  
Estrogen Receptor Positive ◽  
Therapeutic Development

Cyclin E1 is one the most promising biomarkers in estrogen receptor positive (ER+) breast cancer for response to the new standard of care drug class, CDK4/6 inhibitors. Because of its strong predictive value, cyclin E1 expression may be used in the future to triage patients into potential responders and non-responders. Importantly, cyclin E1 is highly related to cyclin E2, and both cyclin E1 and cyclin E2 are estrogen target genes that can facilitate anti-estrogen resistance and can be highly expressed in breast cancer. However cyclin E1 and E2 are often expressed in different subsets of patients. This raises questions about whether the expression of cyclin E1 and cyclin E2 have different biological drivers, if high expressing subsets represent different clinical subtypes, and how to effectively develop a biomarker for E-cyclin expression. Finally, several pan-CDK inhibitors that target cyclin E-CDK2 activity have reached Phase II clinical trials. In this review, we outline the data identifying that different cohorts of patients have high expression of cyclins E1 and E2 in ER+ cancer and address the implications for biomarker and therapeutic development.

scholarly journals In silico Analysis of Combinatorial microRNA Activity Reveals Target Genes and Pathways Associated with Breast Cancer Metastasis

2011 ◽  
Vol 10 ◽  
pp. CIN.S6631 ◽  
Author(s):  
Alan A. Dombkowski ◽  
Zakia Sultana ◽  
Douglas B. Craig ◽  
Hasan Jamil
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Target Genes ◽  
In Silico Analysis ◽  
Metastatic Potential ◽  
Breast Cancer Metastasis ◽  
Computational Method ◽  
Cytoskeleton Organization ◽  
Cellular Processes ◽  
Therapeutic Development

Aberrant microRNA activity has been reported in many diseases, and studies often find numerous microRNAs concurrently dysregulated. Most target genes have binding sites for multiple microRNAs, and mounting evidence indicates that it is important to consider their combinatorial effect on target gene repression. A recent study associated the coincident loss of expression of six microRNAs with metastatic potential in breast cancer. Here, we used a new computational method, miR-AT!, to investigate combinatorial activity among this group of microRNAs. We found that the set of transcripts having multiple target sites for these microRNAs was significantly enriched with genes involved in cellular processes commonly perturbed in metastatic tumors: cell cycle regulation, cytoskeleton organization, and cell adhesion. Network analysis revealed numerous target genes upstream of cyclin D1 and c-Myc, indicating that the collective loss of the six microRNAs may have a focal effect on these two key regulatory nodes. A number of genes previously implicated in cancer metastasis are among the predicted combinatorial targets, including TGFB1, ARPC3, and RANKL. In summary, our analysis reveals extensive combinatorial interactions that have notable implications for their potential role in breast cancer metastasis and in therapeutic development.

scholarly journals Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer

2016 ◽  
Vol 2 (6) ◽  
pp. e1501924 ◽  
Author(s):  
Hari Singhal ◽  
Marianne E. Greene ◽  
Gerard Tarulli ◽  
Allison L. Zarnke ◽  
Ryan J. Bourgo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Tumor Regression ◽  
Progesterone Receptors ◽  
Estrogen Signaling ◽  
Breast Cancers ◽  
Estrogen Action ◽  
Cellular Processes ◽  
Estrogen Receptor Positive ◽  
Estrogen Antagonist

The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER+ (estrogen receptor–positive)/PR+ human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER+/PR+ breast cancers should be explored.

scholarly journals MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5979
Author(s):  
Diana E. Baxter ◽  
Lisa M. Allinson ◽  
Waleed S. Al Amri ◽  
James A. Poulter ◽  
Arindam Pramanik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cell Lines ◽  
Target Genes ◽  
Breast Cancer Cell Lines ◽  
Molecular Characteristics ◽  
Chemotherapy Response ◽  
Breast Cancers ◽  
Microrna Target ◽  
Estrogen Receptor Positive

Background: poor prognosis primary breast cancers are typically treated with cytotoxic chemotherapy. However, recurrences remain relatively common even after this aggressive therapy. Comparison of matched tumours pre- and post-chemotherapy can allow identification of molecular characteristics of therapy resistance and thereby potentially aid discovery of novel predictive markers or targets for chemosensitisation. Through this comparison, we aimed to identify microRNAs associated with chemoresistance, define microRNA target genes, and assess targets as predictors of chemotherapy response. Methods: cancer cells were laser microdissected from matched breast cancer tissues pre- and post-chemotherapy from estrogen receptor positive/HER2 negative breast cancers showing partial responses to epirubicin/cyclophosphamide chemotherapy (n = 5). MicroRNA expression was profiled using qPCR arrays. MicroRNA/mRNA expression was manipulated in estrogen receptor positive/HER2 negative breast cancer cell lines (MCF7 and MDA-MB-175 cells) with mimics, inhibitors or siRNAs, and chemoresponse was assessed using MTT and colony forming survival assays. MicroRNA targets were identified by RNA-sequencing of microRNA mimic pull-downs, and comparison of these with mRNAs containing predicted microRNA binding sites. Survival correlations were tested using the METABRIC expression dataset (n = 1979). Results: miR-195 and miR-26b were consistently up-regulated after therapy, and changes in their expression in cell lines caused significant differences in chemotherapy sensitivity, in accordance with up-regulation driving resistance. SEMA6D was defined and confirmed as a target of the microRNAs. Reduced SEMA6D expression was significantly associated with chemoresistance, in accordance with SEMA6D being a down-stream effector of the microRNAs. Finally, low SEMA6D expression in breast cancers was significantly associated with poor survival after chemotherapy, but not after other therapies. Conclusions: microRNAs and their targets influence chemoresponse, allowing the identification of SEMA6D as a predictive marker for chemotherapy response that could be used to direct therapy or as a target in chemosensitisation strategies.

scholarly journals Stimulation of hERG1 channel activity promotes a calcium-dependent degradation of cyclin E2, but not cyclin E1, in breast cancer cells

Oncotarget ◽  
2015 ◽  
Vol 6 (3) ◽  
pp. 1631-1639 ◽  
Author(s):  
Mathew Perez-Neut ◽  
Andrew Shum ◽  
Bruce D. Cuevas ◽  
Richard Miller ◽  
Saverio Gentile
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Channel Activity ◽  
Cyclin E1 ◽  
Calcium Dependent ◽  
Cyclin E2 ◽  
Herg1 Channel ◽  
Stimulation Of

scholarly journals Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

2019 ◽  
Vol 26 (1) ◽  
pp. R15-R30 ◽  
Author(s):  
Neil Portman ◽  
Sarah Alexandrou ◽  
Emma Carson ◽  
Shudong Wang ◽  
Elgene Lim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Therapy Resistance ◽  
Endocrine Therapy Resistance ◽  
Estrogen Receptor Positive ◽  
Multiple Treatments ◽  
Molecular Landscape

Three inhibitors of CDK4/6 kinases were recently FDA approved for use in combination with endocrine therapy, and they significantly increase the progression-free survival of patients with advanced estrogen receptor-positive (ER+) breast cancer in the first-line treatment setting. As the new standard of care in some countries, there is the clinical emergence of patients with breast cancer that is both CDK4/6 inhibitor and endocrine therapy resistant. The strategies to combat these cancers with resistance to multiple treatments are not yet defined and represent the next major clinical challenge in ER+ breast cancer. In this review, we discuss how the molecular landscape of endocrine therapy resistance may affect the response to CDK4/6 inhibitors, and how this intersects with biomarkers of intrinsic insensitivity. We identify the handful of pre-clinical models of acquired resistance to CDK4/6 inhibitors and discuss whether the molecular changes in these models are likely to be relevant or modified in the context of endocrine therapy resistance. Finally, we consider the crucial question of how some of these changes are potentially amenable to therapy.

scholarly journals Developmental Activation of the Rb–E2F Pathway and Establishment of Cell Cycle-regulated Cyclin-dependent Kinase Activity during Embryonic Stem Cell Differentiation

2005 ◽  
Vol 16 (4) ◽  
pp. 2018-2027 ◽  
Author(s):  
Josephine White ◽  
Elaine Stead ◽  
Renate Faast ◽  
Simon Conn ◽  
Peter Cartwright ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Target Genes ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Cyclin Dependent Kinase ◽  
Pluripotent Cells ◽  
Cyclin E1 ◽  
Cdk2 Activity ◽  
Cycle Dependent

To understand cell cycle control mechanisms in early development and how they change during differentiation, we used embryonic stem cells to model embryonic events. Our results demonstrate that as pluripotent cells differentiate, the length of G1 phase increases substantially. At the molecular level, this is associated with a significant change in the size of active cyclin-dependent kinase (Cdk) complexes, the establishment of cell cycle-regulated Cdk2 activity and the activation of a functional Rb–E2F pathway. The switch from constitutive to cell cycle-dependent Cdk2 activity coincides with temporal changes in cyclin A2 and E1 protein levels during the cell cycle. Transcriptional mechanisms underpin the down-regulation of cyclin levels and the establishment of their periodicity during differentiation. As pluripotent cells differentiate and pRb/p107 kinase activities become cell cycle dependent, the E2F–pRb pathway is activated and imposes cell cycle-regulated transcriptional control on E2F target genes, such as cyclin E1. These results suggest the existence of a feedback loop where Cdk2 controls its own activity through regulation of cyclin E1 transcription. Changes in rates of cell division, cell cycle structure and the establishment of cell cycle-regulated Cdk2 activity can therefore be explained by activation of the E2F–pRb pathway.

scholarly journals Keratin 19 regulates cell cycle pathway and sensitivity of breast cancer cells to CDK inhibitors

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Pooja Sharma ◽  
Sarah Alsharif ◽  
Karina Bursch ◽  
Swetha Parvathaneni ◽  
Dimitrios G. Anastasakis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Structural Integrity ◽  
Cyclin D3 ◽  
Cdk Inhibitors ◽  
Keratin 19

Abstract Keratin 19 (K19) belongs to the keratin family of proteins, which maintains structural integrity of epithelia. In cancer, K19 is highly expressed in several types where it serves as a diagnostic marker. Despite the positive correlation between higher expression of K19 in tumor and worse patient survival, the role of K19 in breast cancer remains unclear. Therefore, we ablated K19 expression in MCF7 breast cancer cells and found that K19 was required for cell proliferation. Transcriptome analyses of KRT19 knockout cells identified defects in cell cycle progression and levels of target genes of E2F1, a key transcriptional factor for the transition into S phase. Furthermore, proper levels of cyclin dependent kinases (CDKs) and cyclins, including D-type cyclins critical for E2F1 activation, were dependent on K19 expression, and K19-cyclin D co-expression was observed in human breast cancer tissues. Importantly, K19 interacts with cyclin D3, and a loss of K19 resulted in decreased protein stability of cyclin D3 and sensitivity of cells towards CDK inhibitor-induced cell death. Overall, these findings reveal a novel function of K19 in the regulation of cell cycle program and suggest that K19 may be used to predict the efficacy of CDK inhibitors for treatments of breast cancer.

scholarly journals Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Kamila Kaminska ◽  
Nina Akrap ◽  
Johan Staaf ◽  
Carla L. Alves ◽  
Anna Ehinger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
In Vitro Models ◽  
Endocrine Treatment ◽  
Cdk Inhibitors ◽  
Cyclin E2

Abstract Background Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself. Methods To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with fulvestrant. Results We found that different in vitro models of fulvestrant resistance show variable stability in their phenotypes, which corresponded with distinct genomic alterations. Notably, the studied models presented adaptation at different cell cycle nodes to facilitate progression through the cell cycle and responded differently to CDK inhibitors. Cyclin E2 overexpression was identified as a biomarker of a persistent fulvestrant-resistant phenotype. Comparison of pre- and post-treatment paired tumor biopsies from patients treated with fulvestrant revealed an upregulation of cyclin E2 upon development of resistance. Moreover, overexpression of this cyclin was found to be a prognostic factor determining resistance to fulvestrant and shorter progression-free survival. Conclusions These data highlight the complexity of estrogen receptor positive breast cancer and suggest that the development of diverse resistance mechanisms dictate levels of ER independence and potentially cross-resistance to CDK inhibitors.

scholarly journals In Silico Prediction for Regulation of Transcription Factors on Their Shared Target Genes Indicates Relevant Clinical Implications in a Breast Cancer Population

2012 ◽  
Vol 11 ◽  
pp. CIN.S8470 ◽  
Author(s):  
Li-Yu D Liu ◽  
Li-Yun Chang ◽  
Wen-Hung Kuo ◽  
Hsiao-Lin Hwa ◽  
Ming-Kwang Shyu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factors ◽  
Target Gene ◽  
Target Genes ◽  
Transcriptional Regulatory Network ◽  
Regulation Of Transcription ◽  
Breast Cancers ◽  
Promoter Regions ◽  
Gene Expressions ◽  
Therapeutic Development

Aberrant transcriptional activities have been documented in breast cancers. Studies often find some transcription factors to be inappropriately regulated and enriched in certain pathological states. The promoter regions of most target genes have binding sites for their transcription factors. An ample of evidence supports their combinatorial effect on their shared target gene expressions. Here, we used a new statistic method, bivariate CID, to predict combinatorial interaction activity between ERα and a transcription factor (E2F1or GATA3 or ERRα) in regulating target gene expression via four regulatory mechanisms. We identified gene sets in three signal transduction pathways perturbed in breast tumors: cell cycle, VEGF, and PDGFRB. Bivariate network analysis revealed several target genes previously implicated in tumor angiogenesis are among the predicted shared targets, including VEGFA, PDGFRB. In summary, our analysis suggests the importance for the multivariate space of an inferred ERα transcriptional regulatory network in breast cancer diagnostic and therapeutic development.

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