ΔNp63, also known as p40, regulates stemness of normal mammary gland epithelium and provides stem cell characteristics in basal and HER2-driven murine breast cancer models. Whilst ΔNp63/p40 is a characteristic feature of normal basal cells and basal-type triple-negative breast cancer, some receptor-positive breast cancers express ΔNp63/p40 and its overexpression imparts cancer stem cell-like properties in ER+ cell lines. However, the incidence of ER+ and HER2+ tumours that express ΔNp63/p40 is unclear and the phenotype of ΔNp63/p40+ cells in these tumours remains uncertain. Using immunohistochemistry with p63 isoform-specific antibodies, we identified a ΔNp63/p40+ tumour cell subpopulation in 100 of 173 (58%) non-triple negative breast cancers and the presence of this population associated with improved survival in patients with ER- /HER2+ tumours (p = 0.006). Furthermore, 41% of ER+ /PR+ and/or HER2+ locally metastatic breast cancers expressed ΔNp63/p40, and these cells commonly accounted for <1% of the metastatic tumour cell population that localised to the tumour/stroma interface, exhibited an undifferentiated phenotype and were CD44+ /ALDH- . In vitro studies revealed that MCF7 and T47D (ER+ ) and BT-474 (HER2+ ) breast cancer cell lines similarly contained a small subpopulation of ΔNp63/p40+ cells that increased in mammospheres. In vivo, MCF7 xenografts contained ΔNp63/p40+ cells with a similar phenotype to primary ER+ cancers. Consistent with tumour samples, these cells also showed a distinct location at the tumour/stroma interface, suggesting a role for paracrine factors in the induction or maintenance of ΔNp63/p40. Thus, ΔNp63/p40 is commonly present in a small population of tumour cells with a distinct phenotype and location in ER+ and/or HER2+ human breast cancers.
- MeSH
- fenotyp MeSH
- heterografty MeSH
- lidé MeSH
- myši MeSH
- nádorové biomarkery analýza metabolismus MeSH
- nádorové kmenové buňky metabolismus patologie MeSH
- nádorové supresorové proteiny metabolismus MeSH
- nádory prsu genetika metabolismus patologie MeSH
- receptor erbB-2 genetika metabolismus MeSH
- receptory pro estrogeny genetika metabolismus MeSH
- transkripční faktory metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Triple-positive breast cancer (TPBC), i.e. HER2-positive (HER2+) and hormone receptors-positive breast cancer, is a specific subgroup of breast cancers. TPBC biology is characterized by strong mutual interactions between signaling pathways stimulated by estrogens and HER2 amplification. The present study aims to carry out a population-based analysis of treatment outcomes in a cohort of hormone receptor (HR) positive and negative breast cancer patients who were treated with anti-HER2 therapy in the Czech Republic. The BREAST research database was used as the data source for this retrospective analysis. The database covers approximately 95% of breast cancer patients treated with targeted therapies in the Czech Republic. The analysis included 6,122 HER2-positive patients. The patients were divided into two groups, based on estrogen receptor (ER) or progesterone receptor (PR) positivity: hormone receptor negative (HR-) patients had both ER- and PR-negative tumors (n=2,518), unlike positive (HR+) patients (n=3,604). HR+ patients were more often diagnosed premenopausal at the time of diagnosis, presented more often at stage I or II and their tumors were less commonly poorly differentiated. The overall survival (OS) was significantly higher in subgroups of HR+ patients according to treatment setting. When evaluated by stages, significantly higher OS was observed in HR+ patients diagnosed at stages II, III, and IV and regardless of tumor grade.
- MeSH
- lidé MeSH
- míra přežití MeSH
- nádorové biomarkery MeSH
- nádory prsu * farmakoterapie genetika MeSH
- prognóza MeSH
- receptor erbB-2 antagonisté a inhibitory genetika MeSH
- receptory pro estrogeny genetika MeSH
- receptory progesteronu genetika MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
The study was focused on assessment of potential health risks of paper-based food contact materials (FCMs) in a step-wise approach using three toxicological bioassays in vitro and chemical analyses of migrating contaminants. 3T3 NRU cytotoxicity test showed high sensitivity to detect basal toxicity of FCMs extracts and served as a first-line test for selection of samples for further testing. The reconstructed human intestine model EpiIntestinal showed more realistic tissue response than cell culture monolayer and higher resistance despite prolonged exposure to the selected 6 samples, i.e. negligible decrease of viability and intestinal penetration, nevertheless an increase of IL-8 after exposure to black printed sample extract. Yeast based assays identified weak agonistic/antagonostic activity to human androgen receptor of the black printed sample. In accordance with the biological effects, the targeted LC and GC analytical methods confirmed the presence of high amounts of phthalates, photoinitiators and PAHs that could justify the hazard of the black printed sample. Heavily printed uncoated FCMs are recognized not to be suitable for direct contact with food. The selected bioassays and chemical analyses might be useful tools to detect targeted biological effects of xenobiotics suspected to contribute to human exposure from food.
- MeSH
- androgenní receptory genetika metabolismus MeSH
- biotest MeSH
- buňky BALB 3T3 MeSH
- cytokiny metabolismus MeSH
- hodnocení rizik MeSH
- intestinální absorpce MeSH
- kontaminace potravin MeSH
- kyseliny ftalové analýza toxicita MeSH
- lidé MeSH
- myši MeSH
- obaly potravin * MeSH
- papír * MeSH
- polycyklické aromatické uhlovodíky analýza toxicita MeSH
- receptory pro estrogeny genetika metabolismus MeSH
- Saccharomyces cerevisiae genetika MeSH
- střevní sliznice účinky léků metabolismus MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants that interact in a complex manner with both the aryl hydrocarbon receptor (AhR) and estrogen receptors (ER). Their potential endocrine-disrupting activities may depend on both inhibitory AhR-ER cross-talk and on AhR-dependent metabolic production of estrogenic PAH metabolites. Here, we analyzed the impact of AhR on estrogen-like effects of PAHs, such as benzo[a]pyrene (BaP), in particular, on control of cell cycle progression/cell proliferation. Using AhR knockout variant of estrogen-sensitive human breast cancer MCF-7 cells (MCF-7 AhRKO cells), we observed that the AhR-dependent control of cytochrome P450 family 1 (CYP1) expression played a major role in formation of estrogenic BaP metabolites, most notably 3-OH-BaP, which contributed to the ER-dependent induction of cell cycle progression/cell proliferation. Both BaP metabolism and the BaP-induced S-phase transition/cell proliferation were inhibited in MCF-7 AhRKO cells, whereas these cells remained sensitive towards both endogenous estrogen 17β-estradiol or hydroxylated BaP metabolites. BaP was found to increase the activity of ER-dependent luciferase reporter gene in wild-type MCF-7 cells; however, unlike its hydroxylated metabolite, BaP failed to stimulate luciferase activity in MCF-7 AhRKO cells. Similarly, estrogen-like effects of other known estrogenic PAHs, such as benz[a]anthracene or 3-methylcholanthrene, were diminished in MCF-7 AhRKO cells. Ectopic expression of human CYP1A1 and CYP1B1 enzymes partly restored both BaP metabolism and its effects on cell proliferation. Taken together, our data suggest that the AhR-dependent metabolism of PAHs contributes significantly to the impact of PAHs on cell proliferation in estrogen-sensitive cells.
- MeSH
- buněčné kultury MeSH
- buněčný cyklus účinky léků genetika MeSH
- cytochrom P-450 CYP1A1 genetika metabolismus MeSH
- cytochrom P450 CYP1B1 genetika metabolismus MeSH
- endokrinní disruptory metabolismus toxicita MeSH
- exprese genu účinky léků MeSH
- genetické vektory MeSH
- genový knockdown MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- plazmidy MeSH
- polycyklické aromatické uhlovodíky metabolismus toxicita MeSH
- proliferace buněk účinky léků genetika MeSH
- receptory aromatických uhlovodíků genetika metabolismus MeSH
- receptory pro estrogeny genetika metabolismus MeSH
- reportérové geny MeSH
- transfekce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Approximately 20 cases of genome-wide uniparental disomy or diploidy (GWUPD) as mosaicism have previously been reported. We present the case of an 11-year-old deaf girl with a paternal uniparental diploidy or isodisomy with a genome-wide loss of heterozygosity (LOH). The patient was originally tested for non-syndromic deafness, and the novel variant p.V234I in the ESRRB gene was found in a homozygous state. Our female proband is the seventh patient diagnosed with GWUPD at a later age and is probably the least affected of the seven, as she has not yet presented any malignancy. Most, if not all, reported patients with GWUPD whose clinical details have been published have developed malignancy, and some of those patient developed malignancy several times. Therefore, our patient has a high risk of malignancy and is carefully monitored by a specific outpatient pediatric oncology program. This observation seems to be novel and unique in a GWUPD patient. Our study is also unique as it not only provides very detailed documentation of the genomic situations of various tissues but also reports differences in the mosaic ratios between the blood and saliva, as well as a normal biparental allelic situation in the skin and biliary duct. Additionally, we were able to demonstrate that the mosaic ratio in the blood remained stable even after 3 years and has not changed over a longer period.
- MeSH
- celogenomová asociační studie MeSH
- diploidie * MeSH
- dítě MeSH
- exprese genu MeSH
- hluchota diagnóza genetika patofyziologie MeSH
- lidé MeSH
- mozaicismus * MeSH
- mutace * MeSH
- nestabilita genomu MeSH
- receptory pro estrogeny genetika MeSH
- rodokmen MeSH
- sekvence nukleotidů MeSH
- sekvenční analýza DNA MeSH
- uniparentální disomie * MeSH
- ztráta heterozygozity MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Resistance to systemic therapy is a major problem in metastatic breast cancer (MBC) that can be explained by initial tumor heterogeneity as well as by evolutionary changes during therapy and tumor progression. Circulating tumor cells (CTCs) detected in a liquid biopsy can be sampled and characterized repeatedly during therapy in order to monitor treatment response and disease progression.Our aim was to investigate how CTC derived gene expression of treatment predictive markers (ESR1/HER2) and other cancer associated markers changed in patient blood samples during six months of first-line systemic treatment for MBC. CTCs from 36 patients were enriched using CellSearch (Janssen Diagnostics) and AdnaTest (QIAGEN) before gene expression analysis was performed with a customized gene panel (TATAA Biocenter).Our results show that antibodies against HER2 and EGFR were valuable to isolate CTCs unidentified by CellSearch and possibly lacking EpCAM expression. Evaluation of patients with clinically different breast cancer subgroups demonstrated that gene expression of treatment predictive markers changed over time. This change was especially prominent for HER2 expression.In conclusion, we found that changed gene expression during first-line systemic therapy for MBC could be a possible explanation for treatment resistance. Characterization of CTCs at several time-points during therapy could be informative for treatment selection.
- MeSH
- chemorezistence MeSH
- dospělí MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádorové biomarkery * MeSH
- nádorové cirkulující buňky metabolismus patologie MeSH
- nádory prsu genetika patologie terapie MeSH
- progrese nemoci MeSH
- receptor erbB-2 genetika MeSH
- receptory pro estrogeny genetika MeSH
- regulace genové exprese u nádorů * MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- staging nádorů MeSH
- stanovení celkové genové exprese MeSH
- transkriptom MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Bisphenol A (BPA), a chemical component of plastics, is a widely distributed environmental pollutant and contaminant of water, air, and food that negatively impacts human health. Concerns regarding BPA have led to the use of BPA-free alternatives, one of which is bisphenol S (BPS). However, the effects of BPS are not well characterized, and its specific effects on reproduction and fertility remain unknown. It is therefore necessary to evaluate any effects of BPS on mammalian oocytes. The present study is the first to demonstrate the markedly negative effects of BPS on pig oocyte maturation in vitro, even at doses lower than those humans are exposed to in the environment. Our results demonstrate (1) an effect of BPS on the course of the meiotic cell cycle; (2) the failure of tubulin fibre formation, which controls proper chromosome movement; (3) changes in the supply of maternal mRNA; (4) changes in the protein amounts and distribution of oestrogen receptors α and β and of aromatase; and (5) disrupted cumulus cell expansion. Thus, these results confirm that BPS is an example of regrettable substitution because this substance exerts similar or even worse negative effects than those of the material it replaced.
- MeSH
- aromatasa genetika MeSH
- buněčná diferenciace účinky léků genetika MeSH
- fenoly farmakologie MeSH
- meióza účinky léků MeSH
- messenger RNA genetika MeSH
- oocyty cytologie účinky léků metabolismus MeSH
- prasata MeSH
- receptory pro estrogeny genetika MeSH
- sulfony farmakologie MeSH
- vývojová regulace genové exprese účinky léků MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Expression of the AGR2 oncogene was shown to be associated with estrogen receptor positive tumors. This gene contributes to enhanced cellular proliferation, drug resistance, metastasis development and may also serve as a predictor of poor prognosis. However, our analysis of AGR2 expression in a subset of estrogen-receptor negative tumors revealed that AGR2 could also be upregulated in hormone-independent manner. AGR2 expression was shown to be significantly increased in HER2 positive breast tumors on both the mRNA and the protein level. Moreover, in a subset of estrogen- and progesterone-receptor negative and simultaneously HER2-positive cases, increased AGR2 expression significantly correlated with worse patient prognosis. Subsequent analysis of independent data sets either collected in our institute or obtained from Oncomine cancer microarray database confirmed all these findings.
- MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory prsu diagnóza genetika MeSH
- prognóza MeSH
- proliferace buněk MeSH
- proteiny genetika metabolismus MeSH
- receptor erbB-2 genetika MeSH
- receptory pro estrogeny genetika MeSH
- regulace genové exprese u nádorů * MeSH
- upregulace MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Breast cancer is the most common and molecularly relatively well characterized malignant disease in women, however, its progression to metastatic cancer remains lethal for 78% of patients 5years after diagnosis. Novel markers could identify the high risk patients and their verification using quantitative methods is essential to overcome genetic, inter-tumor and intra-tumor variability and translate novel findings into cancer diagnosis and treatment. We recently identified 13 proteins associated with estrogen receptor, tumor grade and lymph node status, the key factors of breast cancer aggressiveness, using untargeted proteomics. Here we verified these findings in the same set of 96 tumors using targeted proteomics based on selected reaction monitoring with mTRAQ labeling (mTRAQ-SRM), transcriptomics and immunohistochemistry and validated in 5 independent sets of 715 patients using transcriptomics. We confirmed: (i) positive association of anterior gradient protein 2 homolog (AGR2) and periostin (POSTN) and negative association of annexin A1 (ANXA1) with estrogen receptor status; (ii) positive association of stathmin (STMN1), cofilin-1 (COF1), plasminogen activator inhibitor 1 RNA-binding protein (PAIRBP1) and negative associations of thrombospondin-2 (TSP2) and POSTN levels with tumor grade; and (iii) positive association of POSTN, alpha-actinin-4 (ACTN4) and STMN1 with lymph node status. This study highlights a panel of gene products that can contribute to breast cancer aggressiveness and metastasis, the understanding of which is important for development of more precise breast cancer treatment.
- MeSH
- dospělí MeSH
- faktory depolymerizující aktin biosyntéza genetika MeSH
- invazivní růst nádoru genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfatické metastázy MeSH
- lymfatické uzliny metabolismus patologie MeSH
- molekuly buněčné adheze biosyntéza genetika MeSH
- nádorové biomarkery biosyntéza genetika MeSH
- nádorové proteiny biosyntéza genetika MeSH
- nádory prsu genetika patologie MeSH
- přežití bez známek nemoci MeSH
- prognóza MeSH
- proteiny vázající RNA biosyntéza genetika MeSH
- proteomika MeSH
- receptory pro estrogeny genetika MeSH
- regulace genové exprese u nádorů MeSH
- senioři MeSH
- stathmin biosyntéza genetika MeSH
- thrombospondiny biosyntéza genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
