Cytoplasmic cyclin E is an independent marker of aggressive tumor biology and breast cancer-specific mortality in women over 70 years of age

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Multi-cohort analysis demonstrated that cytoplasmic cyclin E expression in primary breast tumors predicts aggressive disease. However, compared to their younger counterparts, older patients have favorable tumor biology and are less likely to die of breast cancer. Biomarkers therefore require interpretation in this specific context. Here, we assess data on cytoplasmic cyclin E from a UK cohort of older women alongside a panel of >20 biomarkers. Between 1973 and 2010, 813 women ≥70 years of age underwent initial surgery for early breast cancer, from which a tissue microarray was constructed (n = 517). Biomarker expression was assessed by immunohistochemistry. Multivariate analysis of breast cancer-specific survival was performed using Cox’s proportional hazards. We found that cytoplasmic cyclin E was the only biological factor independently predictive of breast cancer-specific survival in this cohort of older women (hazard ratio (HR) = 6.23, 95% confidence interval (CI) = 1.93–20.14; p = 0.002). At ten years, 42% of older patients with cytoplasmic cyclin E-positive tumors had died of breast cancer versus 8% of negative cases (p < 0.0005). We conclude that cytoplasmic cyclin E is an exquisite marker of aggressive tumor biology in older women. Patients with cytoplasmic cyclin E-negative tumors are unlikely to die of breast cancer. These data have the potential to influence treatment strategy in older patients

Cyclin E overexpression sensitizes triple negative breast cancer to Wee1 kinase Inhibition

Purpose: Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in TNBC patients, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775. Experimental Design: Mono and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient derived xenograft (PDX) models with different cyclin E expression profiles. The mechanism(s) of cyclin E-mediated replicative stress were investigated following cyclin E induction or CRISPR/Cas9 knockout by a number of assays in multiple cells lines. Results: Cyclin E overexpression (1) is enriched in TNBCs with high recurrence rates, (2) sensitizes TNBC cell lines and PDX models to AZD1775, (3) leads to CDK2-dependent activation of DNA replication stress pathways and (4) increases Wee1 kinase activity. Moreover, treatment of cells with either CDK2 inhibitors or carboplatin leads to transient transcriptional induction of cyclin E (in cyclin E-low tumors) and result in DNA replicative stress. Such drug mediated cyclin E induction in TNBC cells and PDX models sensitizes them to AZD1775 in a sequential treatment combination strategy. Conclusions: Cyclin E is a potential biomarker of response (1) for AZD1775 as monotherapy in cyclin E high TNBC tumors and (2) for sequential combination therapy with CDK2 inhibitor or carboplatin followed by AZD1775 in cyclin E low TNBC tumors

Paget's disease of the breast

Paget's disease of the breast is a rare type of cancer of the nipple–areola complex and that is often associated with an underlying in situ or invasive carcinoma. This article provides an overview and we review the main clinicopathological and therapeutic features of mammary Paget's disease

Synthesis and Characterization of New Y-shaped Fluorophores with an Imidazole Core

Four new y-shaped fluorophores of 4- {4,5-[2,2'-Bis(2,4,6-trimethoxyphenyl)vinyl]-1-H-imidazole-2-yl}benzonitrile 1a, 2-phenyl-{4,5-[2,2'-Bis(2,4,6-trimethoxyphenyl)vinyl]-1-H-imidazole} 1b, 2- (9-anthryl)-{4,5-[2,2'-Bis(2,4,6-trimethoxyphenyl)vinyl] }-1-H-imidazole 1c and 2- (4-nitrophenyl) - {4,5-[2,2'-Bis(2,4,6-trimethoxyphenyl)vinyl] -1-H-imidazole 1d which bear an imidazole core, were synthesized for the first time via intermediate 1,6-Bis(2,4,6-trimethoxyphenyl)hexa-1,5-diene-3,4-dion with different aldehydes. The structures of the new derivatives were confirmed by H-1 NMR, C-13 NMR and FT-IR. The optical properties such as absorption and emission maxima, Stokes' shift and quantum yield values were investigated in solvents of toluene, tetrahydrofuran and acetonitrile. The products show intense emission maxima in the range of 440-630 nm. The imidazole derivatives exhibited excellent photostabilities

Determination of apoptosis and cell cycle modulators (p16, p21, p27, p53, BCL-2, Bax, BCL-xL, and cyclin D1) in thyroid follicular carcinoma, follicular adenoma, and adenomatous nodules via a tissue microarray method

Background/aim: To identify the role of gene products associated with apoptosis and cell cycle in the pathogenesis of thyroid follicular neoplasm

Targeting Replicative Stress and DNA Repair by Combining PARP and Wee1 Kinase Inhibitors Is Synergistic in Triple Negative Breast Cancers with Cyclin E or BRCA1 Alteration

Simple Summar

Cytoplasmic cyclin E predicts recurrence in patients with breast cancer

Background: Low-molecular-weight-cyclin E (LMW-E) detected by Western blot, predicts for reduced breast cancer survival, however, it is impractical for clinical use. LMW-E lacks a nuclear localization signal which leads to accumulation in the cytoplasm that can be detected by immunohistochemistry. We tested the hypothesis that cytoplasmic staining of cyclin E can be used as a predictor of poor outcome in different subtypes of breast cancer using patient cohorts with distinct clinical and pathologic features. Methods: We evaluated the subcellular localization of cyclin E in breast cancer specimens from 2,494 patients from 4 different cohorts: 303 from a prospective study and 2,191 from retrospective cohorts (National Cancer Institute [NCI], MD Anderson Cancer Center [MDA] and the United Kingdom [UK]). Median follow-up times were 8.0, 10.1, 13.5, and 5.7 years, respectively. Results: Subcellular localization of cyclin E on immunohistochemistry was associated with full-length (nuclear) and low molecular weight isoforms (cytoplasmic) of cyclin E on Western blot analysis. In multivariable analysis, cytoplasmic cyclin E staining was associated with the greatest risk of recurrence compared with other prognostic factors across all subtypes in three (NCI, MDA and UK) of the cohorts. In the MDA cohort, cytoplasmic cyclin E staining outperformed Ki67 and all other variables as prognostic factors. Conclusion: Cytoplasmic cyclin E, identifies patients with the highest likelihood of recurrence consistently across different patient cohorts and subtypes. These patients may benefit from alternative therapies targeting the oncogenic isoforms of cyclin E