basal-like Dotaz Zobrazit nápovědu
Cíl práce: Cílem je podat aktuální, souhrnný a komplexní přehled problematiky basal-like karcinomu prsu se zaměřením na morfologii, molekulární genetiku a klinicko-patologické aspekty týkající se biologie, prognózy a racionální terapie. Typ studie: Souhrnný přehled. Název a sídlo pracoviště: Bioptická laboratoř s.r.o. a Šiklův ústav patologie, LF UK a FN Plzeň. Metodika: Kompilace a setřídění současných literárních faktů, názorů, doporučení a principů v oblasti basal-like karcinomu a jejich aplikace v běžné klinicko-morfologické praxi. Výsledky: Basal-like karcinom prsu je součástí tzv. triple negativních lézí (ER-/PR-/Her2- ) a zahrnuje přibližně 5–7 % všech duktálních karcinomů. Představuje vysoce agresivní nádor s časnou systémovou diseminací, zejména do plic a mozku. Definován je expresí vysokomolekulárních cytokeratinů a téměř u 50 % případů je přítomna dysregulace EGFR, vytvářející potenciál pro cílenou bioterapii inhibitory tyrosin kinázy. Základní morfotyp má podobu medulárního karcinomu s ostrým ohraničením od okolní tkáně a je rovněž typickým představitelem familiárního karcinomu s vrozenou mutací BRCA1 genu. Neinvazivní in situ fáze basal- -like karcinomu je sice vzácná, má však obdobný fenotyp a umožňuje včasnou a spolehlivou diagnostiku z punkční biopsie. Přesná diagnostika tohoto vysoce maligního nádoru dovoluje jednak efektivně monitorovat orgánově specifický metastatický potenciál, jednak vybízí implementovat alternativní terapeutická schémata, jelikož standardní léčebné režimy jsou jen málo účinné.
Objective: Comprehensive review of current topic called basal-like carcinoma of the breast, focused on morphology, molecular biology and clinico-pathological aspects concerning biology, prognosis and rational therapy. Design: Review article. Setting: Biopsy Lab s.r.o. and Šikl's Department of Pathology, Charles University and Faculty Hospital, Pilsen. Methods: Summarized are recent data, diagnostic principals and clinico-pathological recommendations of basal-like carcinoma and outlined is comprehensive guide for daily diagnostic and therapeutic practice. Results: Basal-like carcinoma of the breast is a subset of tripple negative lesions (ER-/PR-/Her2-) and accounts for approximately 5-7% all ductal carcinomas. This is a highly aggressive tumor characterized by rapid systemic dissemination, especially to the lung and brain. By definition, there is expression of high molecular weight cytokeratins and in up to 50% of cases alteration of EGFR gene is found, which creates potential for targeted therapy with tyrosin kinase inhibitors. Basic morphology derives from medullary carcinoma with sharp margin from adjacent parenchyma and presents archetype of BRCA1 mutated familial cancer. Existence of the rare noninvasive in situ phase of the basal-like carcinoma having similar phenotype enables both early and reliable diagnosis even from small core biopsy specimens. Correct diagnosis of this relentless tumor not only brings the chance for effective monitoring specific organs apt to potential metastasis but also challenges for implementation of alternative therapeutic approach, because standard protocols usually fail.
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
Triple-negative breast cancers (TNBC) comprise a heterogeneous subgroup of tumors with a generally poor prognosis. Subclassification of TNBC based on genomic analyses shows that basal-like TNBCs, specifically the basal A or BL2 subtype, are characterized by the expression of ΔNp63, a transcription factor that has been attributed a variety of roles in the regulation of proliferation, differentiation, and cell survival. To investigate the role(s) of p63 in basal-like breast cancers, we used HCC1806 cells that are classified as basal A/BL2. We show that these cells endogenously express p63, mainly as the ΔNp63α isoform. TP63 gene knockout by CRISPR resulted in viable cells that proliferate more slowly and adhere less tightly, with an increased rate of migration. Analysis of adhesion-related gene expression revealed a complex set of alterations in p63-depleted cells, with both increased and decreased adhesion molecules and adhesion substrates compared to parental cells expressing p63. Examination of the phenotype of these cells indicated that endogenous p63 is required to suppress the expression of luminal markers and maintain the basal epithelial phenotype, with increased levels of both CK8 and CK18 and a reduction in N-cadherin levels in cells lacking p63. On the other hand, the level of CK5 was not decreased and ER was not increased, indicating that p63 loss is insufficient to induce full luminal-type differentiation. Taken together, these data demonstrate that p63 exerts multiple pro-oncogenic effects on cell differentiation, proliferation and adhesion in basal-like breast cancers.
- MeSH
- buněčná adheze MeSH
- buněčná diferenciace MeSH
- CD antigeny biosyntéza genetika MeSH
- CRISPR-Cas systémy MeSH
- epitelové buňky metabolismus patologie MeSH
- fenotyp MeSH
- genový knockout MeSH
- kadheriny biosyntéza genetika MeSH
- karcinom patologie MeSH
- keratiny biosyntéza genetika MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny fyziologie MeSH
- nádorové supresorové proteiny nedostatek fyziologie MeSH
- proliferace buněk MeSH
- protein - isoformy fyziologie MeSH
- regulace genové exprese u nádorů MeSH
- transkripční faktory nedostatek fyziologie MeSH
- triple-negativní karcinom prsu patologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: The aim of this study was to devise a molecular classification for salivary duct carcinomas (SDCs) based on the similarities between SDCs and breast carcinomas and on characteristics of the microarray-based gene expression profiling-defined molecular subtypes of breast cancer. METHODS AND RESULTS: Forty-two pure salivary duct carcinomas, 35 of which contained an in-situ component as defined by histological review and/or immunohistochemical analysis, were stained with antibodies for oestrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and cytokeratin (CK) 5/6. Based on these markers, tumours were classified into HER2, luminal androgen receptor-positive, basal-like, luminal and indeterminate phenotype. Analysis revealed that 16.7%, 69%, 4.8%, 9.5% and 0% were of HER2, luminal androgen receptor-positive, basal-like, indeterminate and luminal phenotype, respectively. The in-situ and invasive components displayed the same molecular subtype in all but one case. CONCLUSION: Salivary duct carcinomas can be classified into molecular subgroups approximately equivalent to those in the breast. We also report on the existence of a subgroup of bona fide pure salivary duct carcinomas that have a 'basal-like' phenotype. Understanding the phenotypic complexity of SDCs may help to expedite the identification of novel therapeutic targets for these aggressive tumours.
- MeSH
- androgenní receptory analýza biosyntéza genetika MeSH
- čipová analýza tkání MeSH
- dospělí MeSH
- duktální karcinom klasifikace genetika patologie MeSH
- fenotyp MeSH
- hybridizace in situ MeSH
- imunohistochemie MeSH
- karcinom in situ klasifikace genetika patologie MeSH
- karcinom klasifikace genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery analýza MeSH
- nádory slinných žláz klasifikace genetika patologie MeSH
- receptor erbB-2 analýza biosyntéza genetika MeSH
- sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- transkriptom MeSH
- vývody slinných žláz patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
PURPOSE: The basal-A subtype of triple-negative breast cancer is characterized by high levels of ΔNp63. Various functions have been proposed for p63 in breast cancer initiation and growth, and p63 mediates chemotherapeutic response in a subset of triple-negative breast cancers. We investigated the signaling pathways that are controlled by ΔNp63 in basal-A triple-negative breast cancer. METHODS: Human basal-A triple-negative breast cancer cell lines with ΔNp63α induction or inhibition were studied, along with primary human triple-negative breast cancer tissues. Proteomic, phospho-kinase array, mRNA measurements, and immunohistochemistry were employed. RESULTS: Global phosphoproteomics identified increased EGFR phosphorylation in MDA-MB-468 cells expressing ΔNp63α. ΔNp63α expression increased EGFR mRNA, total EGFR protein, and phospho-EGFR(Y1086), whereas silencing endogenous ΔNp63 in HCC1806 cells reduced both total and phospho-EGFR levels and inhibited the ability of EGF to activate EGFR. EGFR pathway gene expression analysis indicated that ΔNp63 alters EGFR-regulated genes involved in cell adhesion, migration, and angiogenesis. Addition of EGF or neutralizing EGFR antibodies demonstrated that EGFR activation is responsible for ΔNp63-mediated loss of cellular adhesion. Finally, immunohistochemical staining showed that p63-positive triple-negative breast cancers were more likely to express high levels of EGFR than p63-negative cancers, corroborated by in silico analysis of gene expression profiling data. CONCLUSIONS: These data identify EGFR as a major target for ΔNp63 regulation that influences cancer cell adhesion in basal-like triple-negative breast cancer.
- MeSH
- buněčná adheze genetika MeSH
- epidermální růstový faktor genetika metabolismus MeSH
- erbB receptory genetika MeSH
- invazivní růst nádoru genetika MeSH
- lidé MeSH
- membránové proteiny genetika MeSH
- metastázy nádorů MeSH
- nádorové buněčné linie MeSH
- proliferace buněk genetika MeSH
- proteomika MeSH
- regulace genové exprese u nádorů MeSH
- signální transdukce MeSH
- triple-negativní karcinom prsu farmakoterapie genetika patologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Like other malignancies, prostate tumors are thought to contain cancer stem-like cells (CSCs) that are responsible for growth, metastasis, and therapy resistance. ΔNp63 (also called p40) is a regulator of normal prostate stem/progenitor cell activities and a marker of normal basal epithelial cells. The levels of ΔNp63 are reduced in prostate adenocarcinomas, although there is also evidence that ΔNp63 is involved in CSC regulation and drives metastasis to the bone. We studied metastatic deposits of prostate cancers with isoform-specific ΔNp63 and TAp63 antibodies. We identified p63-positive cells in only 3 of 42 metastatic prostate tumors (7%), including 2/38 (5.3%) "usual-type" adenocarcinomas. ΔNp63 and TAp63 isoforms were present in the nuclei of a small subpopulation (< 1%) of tumor cells in these metastases. ΔNp63-positive cells showed a basal-like cell phenotype (cytokeratin 8- and androgen receptor-negative, high molecular weight cytokeratin- and cytokeratin 19-positive), distinct from the tumor bulk. TAp63-positive cells were similar but were sometimes cytokeratin 8-positive. A subset of ΔNp63-positive tumor cells were CD44-positive, a marker of "basal" CSCs but were not positive for the "epithelial" CSC marker ALDH1. TAp63 was not associated with either of these CSC markers. None of the tumors containing p63-positive cells showed evidence of bone metastasis, compared with 28% of the p63-negative tumors. These data show that both ΔNp63 and TAp63 are present in only a small proportion of prostate adenocarcinomas and do not associate with metastasis. The data suggest heterogeneity of CSCs in prostate cancer, similar to other cancer types.
- MeSH
- adenokarcinom metabolismus sekundární MeSH
- dospělí MeSH
- fenotyp MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery metabolismus MeSH
- nádorové kmenové buňky metabolismus patologie MeSH
- nádorové supresorové proteiny metabolismus MeSH
- nádory kostí metabolismus sekundární MeSH
- nádory prostaty metabolismus patologie MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- transkripční faktory metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
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
Neither targeted therapies nor predictors for chemotherapy sensitivity are available for triple-negative breast cancer (TNBC). Our study included 187 patients with TNBC, 164 of whom were treated with anthracycline-based adjuvant chemotherapy. Eleven molecular biomarkers were analyzed. BCL2, epidermal growth factor receptor (EGFR), MYC, TOP2A, and Ki-67 protein expression was evaluated by immunohistochemistry. The status of the EGFR, MYC, and TOP2A genes and chromosomes 7, 8, and 17 was assessed using fluorescence in situ hybridization. High BCL2 expression predicted poor relapse-free survival (RFS) in patients treated with anthracycline-based adjuvant chemotherapy (p = 0.035), poor breast cancer-specific survival (BCSS) (p = 0.048), and a trend to poor overall survival (OS) (p = 0.085). High levels of BCL2 expression predicted poor OS in basal-like (BL) TNBC patients treated with adjuvant anthracycline-based regimens (log-rank p = 0.033, hazard ratio (HR) 3.04, 95 % confidence interval (CI) 1.04-8.91) and a trend to poor RFS (log-rank p = 0.079) and poor BCSS (log-rank p = 0.056). Multivariate analysis showed that BCL2 status, tumor size, and nodal status all had independent predictive significance for RFS (p = 0.005, p = 0.091, p = 0.003, respectively; likelihood ratio test for the whole model, p = 0.003), BCSS (p = 0.012, p = 0.077, p = 0.01, respectively; likelihood ratio test for the whole model, p = 0.016), and OS (p = 0.008, p = 0.004, p = 0.004, respectively; likelihood ratio test for the whole model, p = 0.0006). Similarly, multivariate analysis for BL TNBC showed BCL2, tumor size, and nodal status all had independent predictive significance for RFS (likelihood ratio test for the whole model, p = 0.00125), BCSS (p = 0.00035), and OS (p = 0.00063). High EGFR expression was associated with poor BCSS (p = 0.039) in patients treated with anthracycline-based adjuvant chemotherapy. Patients who underwent anthracycline-based adjuvant chemotherapy and exhibited CMYC amplification had a trend to worse BCSS (p = 0.066). In conclusion, high BCL2 expression is a significant independent predictor of poor outcome in TNBC patients treated with anthracycline-based adjuvant chemotherapy, and this is the first study showing the BCL2 prediction in BL TNBC. BCL2 expression analysis could facilitate decision making on adjuvant treatment in TNBC patients.
- MeSH
- adjuvantní chemoterapie MeSH
- antracykliny aplikace a dávkování MeSH
- dospělí MeSH
- erbB receptory biosyntéza genetika MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie genetika patologie MeSH
- přežití bez známek nemoci MeSH
- protoonkogenní proteiny c-bcl-2 biosyntéza genetika MeSH
- senioři MeSH
- triple-negativní karcinom prsu farmakoterapie genetika patologie 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
Autor popisuje úspěšnou léčbu rozsáhlého tumoru tváře a ucha imiquimodem. Při dlouhodobém sledování je pacient v remisi onemocnění.
The author describes the successful treatment of extensive facial and ear tumor using imiquimod. During the long-term monitoring the patient is in remission.
