scholarly journals Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2268 ◽  
Author(s):  
Christine Lee ◽  
Kristine J. Fernandez ◽  
Sarah Alexandrou ◽  
C. Marcelo Sergio ◽  
Niantao Deng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Strong Association ◽  
Breast Cancers ◽  
Replication Complex ◽  
Cyclin E1 ◽  
Genome Doubling ◽  
Mitotic Slippage ◽  
Whole Genome Doubling ◽  
Cyclin E2 ◽  
Genome Ploidy

Genome doubling is an underlying cause of cancer cell aneuploidy and genomic instability, but few drivers have been identified for this process. Due to their physiological roles in the genome reduplication of normal cells, we hypothesised that the oncogenes cyclins E1 and E2 may be drivers of genome doubling in cancer. We show that both cyclin E1 (CCNE1) and cyclin E2 (CCNE2) mRNA are significantly associated with high genome ploidy in breast cancers. By live cell imaging and flow cytometry, we show that cyclin E2 overexpression promotes aberrant mitosis without causing mitotic slippage, and it increases ploidy with negative feedback on the replication licensing protein, Cdt1. We demonstrate that cyclin E2 localises with core preRC (pre-replication complex) proteins (MCM2, MCM7) on the chromatin of cancer cells. Low CCNE2 is associated with improved overall survival in breast cancers, and we demonstrate that low cyclin E2 protects from excess genome rereplication. This occurs regardless of p53 status, consistent with the association of high cyclin E2 with genome doubling in both p53 null/mutant and p53 wildtype cancers. In contrast, while cyclin E1 can localise to the preRC, its downregulation does not prevent rereplication, and overexpression promotes polyploidy via mitotic slippage. Thus, in breast cancer, cyclin E2 has a strong association with genome doubling, and likely contributes to highly proliferative and genomically unstable breast cancers.

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 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 Neuroglobin: A New Possible Marker of Estrogen-Responsive Breast Cancer

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1986
Author(s):  
Virginia Solar Fernandez ◽  
Marco Fiocchetti ◽  
Manuela Cipolletti ◽  
Marco Segatto ◽  
Paolo Cercola ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
De Novo ◽  
Ductal Carcinoma ◽  
Strong Association ◽  
Therapeutic Interventions ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Data Set

The expression of the α-subtype of Estrogen Receptor (ERα) characterizes most breast cancers (more than 75%), for which endocrine therapy is the mainstay for their treatment. However, a high percentage of ERα+ breast cancers are de novo or acquired resistance to endocrine therapy, and the definition of new targets for improving therapeutic interventions and the prediction of treatment response is demanding. Our previous data identified the ERα/AKT/neuroglobin (NGB) pathway as a common pro-survival process activated in different ERα breast cancer cell lines. However, no in vivo association between the globin and the malignity of breast cancer has yet been done. Here, we evaluated the levels and localization of NGB in ERα+ breast ductal carcinoma tissue of different grades derived from pre-and post-menopausal patients. The results indicate a strong association between NGB accumulation, ERα, AKT activation, and the G3 grade, while no association with the menopausal state has been evidenced. Analyses of the data set (e.g., GOBO) strengthen the idea that NGB accumulation could be linked to tumor cell aggressiveness (high grade) and resistance to treatment. These data support the view that NGB accumulation, mainly related to ER expression and tumor grade, represents a compensatory process, which allows cancer cells to survive in an unfavorable environment.

scholarly journals Classical and Novel Prognostic Markers for Breast Cancer and their Clinical Significance

2010 ◽  
Vol 4 ◽  
pp. CMO.S4773 ◽  
Author(s):  
Pankaj Taneja ◽  
Dejan Maglic ◽  
Fumitake Kai ◽  
Sinan Zhu ◽  
Robert D. Kendig ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Poor Prognosis ◽  
Strong Predictor ◽  
Current Treatment ◽  
Cancer Prognosis ◽  
Breast Cancers ◽  
P53 Mutations ◽  
Breast Cancer Patients ◽  
Poor Prognostic Factor ◽  
Cyclin E1

The use of biomarkers ensures breast cancer patients receive optimal treatment. Established biomarkers such as estrogen receptor (ER) and progesterone receptor (PR) have been playing significant roles in the selection and management of patients for endocrine therapy. HER2 is a strong predictor of response to trastuzumab. Recently, the roles of ER as a negative and HER2 as a positive indicator for chemotherapy have been established. Ki67 has traditionally been recognized as a poor prognostic factor, but recent studies suggest that measurement of Ki67-positive cells during treatment will more effectively predict treatment efficacy for both anti-hormonal and chemotherapy. p53 mutations are found in 20–35% of human breast cancers and are associated with aggressive disease with poor clinical outcome when the DNA-binding domain is mutated. The utility of cyclin D1 as a predictor of breast cancer prognosis is controversial, but cyclin D1b overexpression is associated with poor prognosis. Likewise, overexpression of the low molecular weight form of cyclin E1 protein predicts poor prognosis. Breast cancers from BRCA1/2 carriers often show high nuclear grades, negativity to ER/PR/HER2, and p53 mutations, and thus, are associated with poor prognosis. The prognostic values of other molecular markers, such as p14ARF, TBX2/3, VEGF in breast cancer are also discussed. Careful evaluation of these biomarkers with current treatment modality is required to determine whether their measurement or monitoring offer significant clinical benefits.

Methylation ESR1 as a potential factor of resistence to HER2/neu therapy in patients with breast cancer.

2013 ◽  
Vol 31 (26_suppl) ◽  
pp. 24-24
Author(s):  
Joaquina Martínez-Galán ◽  
Cynthia S. González Rivas ◽  
Julia Ruiz Vozmediano ◽  
Lucia Portellano ◽  
Juan Ramón Delgado
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Strong Association ◽  
Estrogen Therapy ◽  
Therapy Resistance ◽  
Healthy Controls ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Luminal A ◽  
Luminal B

24 Background: Estrogen receptor (ER)-positive breast cancers are considered prognostically more favorable than ER-negative tumors and are often responsive to anti-estrogen therapy. Whereas tumors overexpressing HER2 are endocrine resistant and they require the blockage of the HER2 pathway in addition to estrogen deprivation. To evaluate epigenetics differences in tumor-related genes to ESR1 and HER2/neu status in primary breast cancer is the objective of this study. Methods: We quantified methylation levels of promoter of ERS1 which are to confer growth adventage to cells in 107 women with breast cancer. Real Time QMS-PCR SYBR green (methylation-specific PCR) was used to analyze the hypermethylation. Tumours were classified as phenotype basal, luminal A, Luminal B, and phenotype HER2+. Results: Presence of methylated ESR1 in serum of breast cancer patients was associated with ER-negative phenotype (p=0.0179). Of the available cases, 60 pts (56%) were Luminal A, 10 pts (9.3%) Luminal B, 13 pts (12%) Basal like, and 9 pts (8.4%) HER2+. We observed that methylated ERS1 was preferably associated with phenotype Basal Like and worse interval progression free and survival global though p > 0.05 and the amplification HER2+ was correlation with significant more frequent methylation gene (p<0.05). Thet hypermethylation of normal ERS1 and 14-3-3σ combined differentiated between breast cancer patients and healthy controls (p = 0.0001) with a sensitivity of 81% (95% CI: 72–88%) and specificity of 88% (95% CI: 78–94%). Conclusions: This study identifies the presence of variations in global levels of methylation promoters genes in healthy controls and breast cancer with different phenotype classes and shows that these differences have clinical significance. These showed that frequent methylation had a strong association with molecular phenotype of breast cancer and perhaps in the future can explain therapy resistance related to RE and HER2/neu status and this may be of significance in the assessment of targeted therapy resistance related to ER and HER2/neu status in breast cancer patients.

scholarly journals PD-L1 Protein Expression in Middle Eastern Breast Cancer Predicts Favorable Outcome in Triple-Negative Breast Cancer

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 229
Author(s):  
Sandeep Kumar Parvathareddy ◽  
Abdul K. Siraj ◽  
Saeeda O. Ahmed ◽  
Laila Omar Ghazwani ◽  
Saud M. Aldughaither ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Mismatch Repair ◽  
Triple Negative ◽  
Middle Eastern ◽  
Strong Association ◽  
Treatment Strategies ◽  
Prognostic Indicators ◽  
Breast Cancers ◽  
Ki 67

Programmed cell-death ligand 1 (PD-L1) has been shown to induce potent T-cell mediated anti-tumoral immunity. The significance of PD-L1 expression in the prognosis of breast cancer (BC) remains controversial and its prevalence and prognostic value in breast cancer from Middle Eastern ethnicity is lacking. A total of 1003 unselected Middle Eastern breast cancers were analyzed for PD-L1 expression using immunohistochemistry. PD-L1 expression, seen in 32.8% (329/1003) of cases, was significantly associated with poor prognostic indicators such as younger patients, high-grade tumors, estrogen-receptor (ER)-negative, progesterone-receptor (PR)-negative, and triple-negative breast cancers (TNBC) as well as high Ki-67 index. We also found a significant association between PD-L1 expression and deficient mismatch repair protein expression. No association was found between PD-L1 expression and clinical outcome. However, on further subgroup analysis, PD-L1 expression was found to be an independent marker for favorable overall survival and recurrence-free survival in TNBC. In conclusion, we demonstrated strong association between PD-L1 and mismatch repair deficiency in Middle Eastern BC patients and that PD-L1 overexpression in tumor cells was an independent prognostic marker in TNBCs from Middle Eastern ethnicity. Overall, these findings might help in the development of more appropriate treatment strategies for BC in Middle Eastern population.

scholarly journals Differential whole-genome doubling and homologous recombination deficiencies across breast cancer subtypes from the Taiwanese population

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Chia-Hsin Wu ◽  
Chia-Shan Hsieh ◽  
Yo-Cheng Chang ◽  
Chi-Cheng Huang ◽  
Hsien-Tang Yeh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
De Novo ◽  
Chromosome Complement ◽  
Breast Cancer Subtypes ◽  
Whole Genome ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Genome Doubling ◽  
Whole Genome Doubling

AbstractWhole-genome doubling (WGD) is an early macro-evolutionary event in tumorigenesis, involving the doubling of an entire chromosome complement. However, its impact on breast cancer subtypes remains unclear. Here, we performed a comprehensive and quantitative analysis of WGD and its influence on breast cancer subtypes in patients from Taiwan and consequently highlight the genomic association between WGD and homologous recombination deficiency (HRD). A higher manifestation of WGD was reported in triple-negative breast cancer, conferring high chromosomal instability (CIN), while HER2 + tumors exhibited early WGD events, with widely varied CIN levels, compared to luminal-type tumors. An association of higher activity of de novo indel signature 2 with WGD and HRD in Taiwanese breast cancer patients was reported. A control test between WGD and pseudo non-WGD samples was further employed to support this finding. The study provides a better comprehension of tumorigenesis in breast cancer subtypes, thus assisting in personalized treatment.

scholarly journals Aurantoside C Targets and Induces Apoptosis in Triple Negative Breast Cancer Cells

Marine Drugs ◽  
2018 ◽  
Vol 16 (10) ◽  
pp. 361 ◽  
Author(s):  
Sumi Shrestha ◽  
Anabel Sorolla ◽  
Jane Fromont ◽  
Pilar Blancafort ◽  
Gavin Flematti
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Anticancer Agents ◽  
Breast Cancer Cells ◽  
Cytotoxic Effect ◽  
Triple Negative ◽  
Cytotoxic Activities ◽  
Chemotherapeutic Drugs ◽  
Breast Cancers ◽  
Cyclin E1

Triple negative breast cancer (TNBC) is a subtype of breast cancers that currently lacks effective targeted therapy. In this study, we found that aurantoside C (C828), isolated from the marine sponge Manihinea lynbeazleyae collected from Western Australia, exhibited higher cytotoxic activities in TNBC cells compared with non-TNBC (luminal and normal-like) cells. The cytotoxic effect of C828 was associated to the accumulation of cell at S-phase, resulting in the decline of cyclin D1, cyclin E1, CDK4, and CDK6, and an increase in p21. We also found that C828 inhibited the phosphorylation of Akt/mTOR and NF-kB pathways and increased the phosphorylation of p38 MAPK and SAPK/JNK pathways, leading to apoptosis in TNBC cells. These effects of C828 were not observed in non-TNBC cells at the concentrations that were cytotoxic to TNBC cells. When compared to the cytotoxic effect with the chemotherapeutic drugs doxorubicin and cisplatin, C828 was found to be 20 times and 35 times more potent than doxorubicin and cisplatin, respectively. These results indicate that C828 could be a promising lead for developing new anticancer agents that target TNBC cells.

Mechanisms underlying uncontrolled genome doubling in breast cancer

2019 ◽  
Author(s):  
Christine S Lee ◽  
Samuel Rogers ◽  
Kristine Fernandez ◽  
Sarah Alexandrou ◽  
Niantao Deng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genome Doubling

Prognostic Role of Hedgehog-GLI1 Signaling Pathway in Aggressive and Metastatic Breast Cancers

2020 ◽  
Vol 21 (1) ◽  
pp. 33-43 ◽  
Author(s):  
Prasuja Rokkam ◽  
Shailender Gugalavath ◽  
Deepak Kakara Gift Kumar ◽  
Rahul Kumar Vempati ◽  
Rama Rao Malla
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Neural Development ◽  
Splice Variants ◽  
Metastatic Breast ◽  
Basic Function ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Aberrant Expression ◽  
Cellular Processes

Glioma-associated oncogene homolog 1 (GLI1) is reported as an amplified gene in human glioblastoma cells. It is a krupple like transcription factor, belonging to the zinc finger family. The basic function of GLI1 is normal neural development at various stages of human. The GLI1 gene was first mapped on the chromosome sub-bands 12q13.3-14.1. Further, single nucleotide polymorphism is mostly observed in translating a region of 5’ and 3’- UTR of GLI1 gene in addition to two post-transcriptional splice variants, GLIΔN and tGLI. Additionally, it also regulates a plethora of gene which mediates crucial cellular processes like proliferation, differentiation, oncogenesis, EMT, and metastasis. It also regulates tumor tolerance, chemoresistance, and radioresistance. Aberrant expression of GLI1 predicts the poor survival of breast cancer patients. GLI1 is an essential mediator of the SHH signaling pathway regulating self-renewal of stem cells, angiogenesis, and expression of FOXS1, CYR61. GLI1 mediated HH pathway can induce apoptosis. Hence, GLI1 can be a future diagnostic, prognostic marker, and as well as a potent target of therapeutics in breast cancer.

Sign in / Sign up

Export Citation Format

Share Document