OBJECTIVE: The prognostic relevance of hormonal biomarkers in endometrial cancer (EC) has been well-established. A refined three-tiered risk model for estrogen receptor (ER)/progesterone receptor (PR) expression was shown to improve prognostication. This has not been evaluated in relation to the molecular subgroups. This study aimed to evaluate the ER/PR expression within the molecular subgroups in EC. METHODS: A retrospective multicenter cohort study was performed and data from the European Network for Individualized Treatment centers and Vancouver, Canada were used. ER/PR immunohistochemical expression was grouped as: ER/PR 0-10 %, 20-80 % or 90-100 %. Molecular subgroups were determined with full next-generation sequencing or combined with immunohistochemistry: POLEmut, mismatch repair deficient (MMRd), p53mut and no-specific molecular profile (NSMP). RESULTS: A total of 739 patients were included (median follow-up 5.0 years). Tumors were classified as POLEmut in 9.1 %(N = 67), MMRd in 27.6 %(N = 204), p53mut in 20.8 %(N = 154) and NSMP in 42.5 %(N = 314). Among all molecular subgroups, patients with ER/PR 90-100 % expression revealed the best disease-specific survival (DSS). Within p53mut, PR 90-100 % expression showed a 5-year DSS of 100.0 %. ER expression is prognostic more relevant in MMRd and NSMP tumors while PR expression in p53mut and NSMP tumors. Across all molecular subgroups, PR 0-10 %, p53mut, lympho-vascular space invasion and FIGO stage III-IV remained independently prognostic for reduced DSS Whereas PR 90-100 % and POLEmut remained independently prognostic for improved DSS. CONCLUSION: We demonstrated that ER/PR expression remain prognostically relevant within the molecular subgroups, and that a three-tiered cutoff refines prognostication. These data support incorporating routine evaluation of ER/PR expression in clinical practice.

• Klíčová slova
• Biomarkers, Endometrial carcinoma, Immunohistochemical, Molecular classification, Pathology, Prognosis,
• MeSH
• dospělí MeSH
• imunohistochemie MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery * metabolismus   genetika   MeSH
• nádorový supresorový protein p53 metabolismus   genetika   MeSH
• nádory endometria * metabolismus   patologie   genetika   mortalita   MeSH
• prognóza MeSH
• receptory pro estrogeny * metabolismus   biosyntéza   MeSH
• receptory progesteronu * metabolismus   biosyntéza   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři 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
• multicentrická studie MeSH
• Názvy látek
• nádorové biomarkery * MeSH
• nádorový supresorový protein p53 MeSH
• receptory pro estrogeny * MeSH
• receptory progesteronu * MeSH

G protein-coupled estrogen receptor 1 (GPER-1) has gained recognition for its role in conferring cardioprotection. However, the extent to which GPER-1 exerts equally important effects in both sexes remains unclear. The study found similar expressions of GPER-1 in rat heart apex in both sexes. In male rats, administering epinephrine (Epi) at a dose of 31.36 microg/100 g resulted in a rapid decline in cardiac function, accompanied by a sharp increase in bax/bcl-2 levels. In contrast, female rats did not display significant changes in cardiac function under the same conditions. Additionally, compared to the injection of Epi alone (at a dose of 15.68 microg/100 g), the administration of G15 (GPER-1 antagonist) further decreased cardiac function in both male and female rats. However, it only increased mortality and lung coefficient in male rats. Conversely, G1 (GPER-1 agonist) administration improved cardiac function in both sexes. Notably, the apex of the male heart exhibited lower levels of inhibitory G protein (Galphai). Furthermore, female and male rats treated with Epi displayed elevated phosphorylated protein kinase B (p-Akt). Compared to their respective Epi groups, the administration of G15 increased p-Akt levels in female rat hearts but decreased them in male rat hearts. Conversely, the administration of G1 decreased p-Akt levels in females but rapidly increased them in male rats. Our study uncovers the vital role of GPER-1 in protecting against stress-induced heart injuries in a sex-specific manner. These findings hold immense potential for advancing targeted cardiac therapies and enhancing outcomes for both females and males.

• MeSH
• adrenalin MeSH
• fyziologický stres fyziologie   MeSH
• krysa rodu Rattus MeSH
• pohlavní dimorfismus MeSH
• potkani Sprague-Dawley * MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• receptory spřažené s G-proteiny * metabolismus   MeSH
• sexuální faktory MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adrenalin MeSH
• Gper1 protein, rat MeSH Prohlížeč
• protoonkogenní proteiny c-akt * MeSH
• receptory pro estrogeny MeSH
• receptory spřažené s G-proteiny * MeSH

BACKGROUND: Resistance to endocrine therapies in hormone receptor-positive breast cancer is challenging. We aimed to assess the next-generation oral selective oestrogen receptor degrader (SERD) and complete oestrogen receptor antagonist, camizestrant, versus the first-approved SERD, fulvestrant, in post-menopausal women with oestrogen receptor-positive, HER2-negative, advanced breast cancer. METHODS: SERENA-2 is an open-label, randomised, phase 2 trial that is being conducted at 74 study centres across Asia, Europe, the Middle East, and North America. Female patients aged 18 years or older who were post-menopausal with histologically or cytologically confirmed metastastic or locoregional oestrogen receptor-positive, HER2-negative breast cancer, an Eastern Cooperative Oncology Group or WHO performance status of 0 or 1, and disease recurrence or progression on at least one line of endocrine therapy, and no more than one previous endocrine therapy in the advanced setting. Patients were initially randomly assigned (1:1:1:1) to receive oral camizestrant once daily at 75 mg, 150 mg, or 300 mg (until the 300 mg group was closed), or fulvestrant intramuscularly at 500 mg (per label). Randomisation was managed through an interactive web-based system and stratified by previous treatment with CDK4/6 inhibitors and presence of liver and/or lung metastases. The primary objective was to determine clinical efficacy of camizestrant versus fulvestrant at each dose level using the primary endpoint of investigator-assessed progression-free survival, per Response Evaluation Criteria in Solid Tumours (version 1.1), assessed by intention to treat in all randomly assigned patients (full analysis set). No formal statistical comparison for the efficacy analysis of the camizestrant 300 mg dose versus fulvestrant was to be performed. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04214288, and is ongoing. FINDINGS: Between May 11, 2020, and Aug 10, 2021, 240 patients were randomly assigned to receive camizestrant 75 mg (n=74), 150 mg (n=73), 300 mg (n=20), or fulvestrant (n=73), and were included in the full analysis set. All patients received at least one dose of study drug. Median follow-up was 16·6 months (IQR 12·9-19·4) for the camizestrant 75 mg group, 16·3 months (12·9-18·3) for the camizestrant 150 mg group, and 14·7 months (12·7-20·1) for the fulvestrant 500 mg group. Median progression-free survival was 7·2 months (90% CI 3·7-10·9) with camizestrant 75 mg, 7·7 months (5·5-12·9) with camizestrant 150 mg, and 3·7 months (2·0-6·0) with fulvestrant. The hazard ratio for camizestrant 75 mg versus fulvestrant was 0·59 (90% CI 0·42-0·82; p=0·017), and the hazard ratio for camizestrant 150 mg versus fulvestrant was 0·64 (0·46-0·89; p=0·0090). Treatment-related adverse events occurred in 39 (53%) of 74 patients in the camizestrant 75 mg group, 49 (67%) of 73 patients in the camizestrant 150 mg group, 14 (70%) of 20 patients in the camizestrant 300 mg group, and 13 (18%) of 73 patients in the fulvestrant group. No single grade 3 or worse treatment-emergent adverse event occurred in more than two (3%) patients in any group. Serious treatment-emergent adverse events occurred in six (8%) patients in the camizestrant 75 mg group, seven (10%) patients in the camizestrant 150 mg group, two (10%) patients in the camizestrant 300 mg group, and four (5%) patients in the fulvestrant group. No treatment-related deaths occurred. INTERPRETATION: Camizestrant at 75 and 150 mg showed a significant benefit in progression-free survival versus fulvestrant. These results support further development of camizestrant for the treatment of oestrogen receptor-positive, HER2-negative breast cancer. FUNDING: AstraZeneca.

• MeSH
• antagonisté estrogenového receptoru aplikace a dávkování   terapeutické užití   MeSH
• antitumorózní látky hormonální aplikace a dávkování   terapeutické užití   MeSH
• aplikace orální MeSH
• azetidiny MeSH
• dospělí MeSH
• fulvestrant * aplikace a dávkování   MeSH
• isochinoliny MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu * farmakoterapie   patologie   mortalita   MeSH
• postmenopauza * MeSH
• receptor erbB-2 * analýza   metabolismus   MeSH
• receptory pro estrogeny * metabolismus   analýza   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• antagonisté estrogenového receptoru MeSH
• antitumorózní látky hormonální MeSH
• AZD9833 MeSH Prohlížeč
• azetidiny MeSH
• ERBB2 protein, human MeSH Prohlížeč
• fulvestrant * MeSH
• isochinoliny MeSH
• receptor erbB-2 * MeSH
• receptory pro estrogeny * MeSH

AIM: The effect of platelet-rich autoplasma on endometrial thickness and receptor sensitivity to estrogen and progesterone. MATERIALS AND METHODS: This prospective clinical study included 200 patients. The participants in the study were divided into two groups. The first control group received hormone replacement therapy (HRT). The second study group received an intrauterine infusion of platelet-rich autoplasma (PRP group). On the 19th day of the menstrual cycle, an ultrasound examination was performed to assess endometrial thickness, as well as an immunohistochemical analysis to determine receptor sensitivity to estrogen and progesterone. RESULTS: In the course of the study, we found that the use of platelet-rich autoplasma increased the thickness of the endometrium by 0.85 mm; the average thickness of the endometrium in the group who received PRP therapy was 8.25 (8.25-8.61) mm; and in the group of patients who only received HRT, it was 7.40 (7.34-7.65) mm. The sensitivity of receptors to estrogen in the experimental group increased by 3.5, in the experimental group it was 75.00 (71.43-74.22), and in the control group it was 71.50 (67.05-70.85). The sensitivity of receptors to progesterone also increased by 9.0, in the experimental group it was 95.0 (91.4-93.8), and in the control group it was 86.0 (83.47-86.27). CONCLUSION: Due to the action of platelet factors, PRP therapy has a positive effect on the endometrium, increasing its thickness and improving its receptivity. Therefore, it can be concluded that this method can find great practical application to improve the outcomes of assisted reproductive technology programs.

• Klíčová slova
• infertility, platelet-rich autoplasma, thin endometrium,
• MeSH
• dospělí MeSH
• endometrium * diagnostické zobrazování   metabolismus   účinky léků   MeSH
• estrogeny MeSH
• lidé MeSH
• plazma bohatá na destičky MeSH
• progesteron * MeSH
• prospektivní studie MeSH
• receptory pro estrogeny metabolismus   MeSH
• receptory progesteronu metabolismus   MeSH
• trombocyty metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• estrogeny MeSH
• progesteron * MeSH
• receptory pro estrogeny MeSH
• receptory progesteronu MeSH

Estrogen receptor alpha (ER) is a key biomarker for breast cancer, and the presence or absence of ER in breast and other hormone-dependent cancers decides treatment regimens and patient prognosis. ER is activated after ligand binding - typically by steroid. 2682 steroid compounds were used in a molecular docking study to identify novel ligands for ER and to predict compounds that may show anticancer activity. The effect of the most promising compounds was determined by a novel luciferase reporter assay. Two compounds, 7 and 12, showing ER inhibitory activity comparable to clinical inhibitors such as tamoxifen or fulvestrant were selected. We propose that the inhibitory effect of compounds 7 and 12 on ER is related to the presence of a double bond in their D-ring, which may protect against ER activation by reducing the electron density of the keto group, or may undergo metabolism leading to an active compound. Western blotting revealed that compound 12 decreased the level of ER in the breast cancer cell line MCF7, which was associated with reduced expression of both isoforms of the progesterone receptor, a well-known downstream target of ER. However, compound 12 has a different mechanism of action from fulvestrant. Furthermore, we found that compound 12 interferes with mitochondrial functions, probably by disrupting the electron transport chain, leading to induction of the intrinsic apoptotic pathway even in ER-negative breast cancer cells. In conclusion, the combination of computational and experimental methods shown here represents a rapid approach to determine the activity of compounds towards ER. Our data will not only contribute to research focused on the regulation of ER activity but may also be useful for the further development of novel steroid receptor-targeted drugs applicable in clinical practice.

• Klíčová slova
• Apoptosis, Docking of steroid library, Estrogen receptor alpha, Luciferase assay, Mitochondrial membrane potential,
• MeSH
• alfa receptor estrogenů genetika   metabolismus   MeSH
• estradiol farmakologie   terapeutické užití   MeSH
• estron * farmakologie   MeSH
• fulvestrant farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prsu * farmakoterapie   metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• simulace molekulového dockingu MeSH
• tamoxifen farmakologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alfa receptor estrogenů MeSH
• estradiol MeSH
• estron * MeSH
• fulvestrant MeSH
• receptory pro estrogeny MeSH
• tamoxifen MeSH

Oxysterols play significant roles in many physiological and pathological processes including cancer. They modulate some of the cancer hallmarks pathways, influence the efficacy of anti-cancer drugs, and associate with patient survival. In this study, we aimed to analyze the role of 7-ketocholesterol (7-KC) in breast carcinoma cells and its potential modulation of the tamoxifen effect. 7-KC effects were studied in two estrogen receptor (ER)-positive (MCF-7 and T47D) and one ER-negative (BT-20) breast cancer cell lines. First, we tested the viability of cells in the presence of 7-KC. Next, we co-incubated cells with tamoxifen and sublethal concentrations of 7-KC. We also tested changes in caspase 3/7 activity, deregulation of the cell cycle, and changes in expression of selected genes/proteins in the presence of tamoxifen, 7-KC, or their combination. Finally, we analyzed the effect of 7-KC on cellular migration and invasion. We found that the presence of 7-KC slightly decreases the efficacy of tamoxifen in MCF-7 cells, while an increased effect of tamoxifen and higher caspase 3/7 activity was observed in the BT-20 cell line. In the T47D cell line, we did not find any modulation of tamoxifen efficacy by the presence of 7-KC. Expression analysis showed the deregulation in CYP1A1 and CYP1B1 with the opposite trend in MCF-7 and BT-20 cells. Moreover, 7-KC increased cellular migration and invasion potential regardless of the ER status. This study shows that 7-KC can modulate tamoxifen efficacy as well as cellular migration and invasion, making 7-KC a promising candidate for future studies.

• Klíčová slova
• 7-ketocholesterol, Breast cancer, Migration, Proliferation, Tamoxifen,
• MeSH
• antitumorózní látky hormonální farmakologie   MeSH
• chemorezistence MeSH
• kaspasa 3 genetika   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• nádorové buněčné linie MeSH
• nádory prsu * farmakoterapie   MeSH
• proliferace buněk MeSH
• receptory pro estrogeny metabolismus   MeSH
• tamoxifen * farmakologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-ketocholesterol MeSH Prohlížeč
• antitumorózní látky hormonální MeSH
• kaspasa 3 MeSH
• receptory pro estrogeny MeSH
• tamoxifen * MeSH

PURPOSE: Amcenestrant (oral selective estrogen receptor degrader) demonstrated promising safety and efficacy in earlier clinical studies for endocrine-resistant, estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (aBC). PATIENTS AND METHODS: In AMEERA-3 (ClinicalTrials.gov identifier: NCT04059484), an open-label, worldwide phase II trial, patients with ER+/HER2- aBC who progressed in the (neo)adjuvant or advanced settings after not more than two previous lines of endocrine therapy (ET) were randomly assigned 1:1 to amcenestrant or single-agent endocrine treatment of physician's choice (TPC), stratified by the presence/absence of visceral metastases, previous/no treatment with cyclin-dependent kinase 4/6 inhibitor, and Eastern Cooperative Oncology Group performance status (0/1). The primary end point was progression-free survival (PFS) by independent central review, compared using a stratified log-rank test (one-sided type I error rate of 2.5%). RESULTS: Between October 22, 2019, and February 15, 2021, 290 patients were randomly assigned to amcenestrant (n = 143) or TPC (n = 147). PFS was numerically similar between amcenestrant and TPC (median PFS [mPFS], 3.6 v 3.7 months; stratified hazard ratio [HR], 1.051 [95% CI, 0.789 to 1.4]; one-sided P = .643). Among patients with baseline mutated ESR1; (n = 120 of 280), amcenestrant numerically prolonged PFS versus TPC (mPFS, 3.7 v 2.0 months; stratified HR, 0.9 [95% CI, 0.565 to 1.435]). Overall survival data were immature but numerically similar between groups (HR, 0.913; 95% CI, 0.595 to 1.403). In amcenestrant versus TPC groups, treatment-emergent adverse events (any grade) occurred in 82.5% versus 76.2% of patients and grade ≥3 events occurred in 21.7% versus 15.6%. CONCLUSION: AMEERA-3 did not meet its primary objective of improved PFS with amcenestrant versus TPC although a numerical improvement in PFS was observed in patients with baseline ESR1 mutation. Efficacy and safety with amcenestrant were consistent with the standard of care for second-/third-line ET for ER+/HER2- aBC.

• MeSH
• lidé MeSH
• nádory prsu * patologie   MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   MeSH
• receptor erbB-2 metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• ERBB2 protein, human MeSH Prohlížeč
• receptor erbB-2 MeSH
• receptory pro estrogeny MeSH

The oestrogen receptor (ER) from the nuclear receptor family is involved in different physiological processes, which can be affected by multiple xenobiotics. Some of these compounds, such as bisphenols, pesticides, and phthalates, are widespread as consequence of human activities and are commonly present also in human organism. Xenobiotics able to interact with ER and trigger a hormone-like response, are known as endocrine disruptors. In this review, we aim to summarize the available knowledge on products derived from human industrial activity and other xenobiotics reported to interact with ER. ER-disrupting chemicals behave differently towards oestrogen-dependent cell lines than endogenous oestradiol. In low concentrations, they stimulate proliferation, whereas at higher concentrations, are toxic to cells. In addition, most of the knowledge on the topic is based on individual compound testing, and only a few studies assess xenobiotic combinations, which better resemble real circumstances. Confirmation from in vivo models is lacking also.

• Klíčová slova
• Endocrine disruptors, Oestradiol, Oestrogen receptors, Pollutants, Xenobiotics,
• MeSH
• endokrinní disruptory * toxicita   MeSH
• estradiol MeSH
• estrogeny toxicita   MeSH
• lidé MeSH
• receptory pro estrogeny * metabolismus   MeSH
• xenobiotika toxicita   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• endokrinní disruptory * MeSH
• estradiol MeSH
• estrogeny MeSH
• receptory pro estrogeny * MeSH
• xenobiotika MeSH

BACKGROUND: Carcinoma with apocrine differentiation (AC) is a subtype of breast carcinoma with apocrine features in >90% of the tumor. Molecular studies demonstrate AC has high expression of androgen receptor (AR) mRNA. Pure AC lack estrogen receptor (ER), progesterone receptor (PR), and express AR, with variable human epidermal growth factor 2 (HER2) status. Currently, in triple negative AC, no targetable therapies or specific diagnostic markers exist. MATERIALS AND METHODS: α-Methylacyl CoA racemase (AMACR) expression was investigated as a marker of apocrine differentiation using a single-plex immunoperoxidase stain, and a novel AMACR/p63 dual stain in a subset of cases, across 1) benign apocrine lesions (apocrine metaplasia, adenosis) 2) apocrine DCIS (ADCIS), 3) AC/ invasive ductal carcinoma (IDC) with apocrine features, 4) non-apocrine triple negative breast cancer (TNBC) and 5) IDC, no special type. A sub-set of cases were evaluated by tissue microarray. RESULTS: AMACR expression was increased in both AC and ADCIS, with minimal expression in benign breast tissue, TNBC and IDC, NST cases. In invasive cases, those with positive AMACR (>5% positivity) were significantly associated with higher histologic grade (P = .006), initial N stage (chi squared 0.044), and lack of ER or PR expression (both P < .001), with no correlation with overall survival. Analysis of TCGA breast cancer datasets revealed AMACR expression was significantly higher in molecularly defined apocrine carcinomas relative to basal and luminal subtypes. Moreover, high AMACR expression predicted worse relapse-free and distant-metastasis free survival, among both ER-/PR-/Her2- and ER-/PR-/Her2+ breast cancer cohorts (log-rank P = .081 and .00011, respectively). CONCLUSION: AMACR represents a promising diagnostic and prognostic marker in apocrine breast lesions. Further study is needed to determine the biologic and clinical significance of this protein in AC.

• Klíčová slova
• AMACR, Alpha-methylacyl CoA racemase, Apocrine breast cancer, Breast Pathology, Immunohistochemistry,
• MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• lymfatické metastázy MeSH
• nádorové biomarkery metabolismus   MeSH
• nádory prsu * metabolismus   MeSH
• racemasy a epimerasy MeSH
• receptor erbB-2 metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• receptory progesteronu metabolismus   MeSH
• triple-negativní karcinom prsu * diagnóza   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové biomarkery MeSH
• racemasy a epimerasy MeSH
• receptor erbB-2 MeSH
• receptory pro estrogeny MeSH
• receptory progesteronu MeSH

Catechol-O-methyl transferase (COMT) is involved in detoxification of catechol estrogens, playing cancer-protective role in cells producing or utilizing estrogen. Moreover, COMT suppressed migration potential of breast cancer (BC) cells. To delineate COMT role in metastasis of estrogen receptor (ER) dependent BC, we investigated the effect of COMT overexpression on invasion, transcriptome, proteome and interactome of MCF7 cells, a luminal A BC model, stably transduced with lentiviral vector carrying COMT gene (MCF7-COMT). 2D and 3D assays revealed that COMT overexpression associates with decreased cell invasion (p < 0.0001 for Transwell assay, p < 0.05 for spheroid formation). RNA-Seq and LC-DIA-MS/MS proteomics identified genes associated with invasion (FTO, PIR, TACSTD2, ANXA3, KRT80, S100P, PREX1, CLEC3A, LCP1) being downregulated in MCF7-COMT cells, while genes associated with less aggressive phenotype (RBPMS, ROBO2, SELENBP, EPB41L2) were upregulated both at transcript (|log2FC|> 1, adj. p < 0.05) and protein (|log2FC|> 0.58, q < 0.05) levels. Importantly, proteins driving MET signaling were less abundant in COMT overexpressing cells, and pull-down confirmed interaction between COMT and Kunitz-type protease inhibitor 2 (SPINT2), a negative regulator of MET (log2FC = 5.10, q = 1.04-7). In conclusion, COMT may act as tumor suppressor in ER dependent BC not only by detoxification of catechol estrogens but also by suppressing cell invasion and interplay with MET pathway.

• MeSH
• estrogeny metabolismus   MeSH
• katechol-O-methyltransferasa * genetika   MeSH
• katecholestrogeny MeSH
• katecholy MeSH
• nádory * MeSH
• receptory pro estrogeny metabolismus   MeSH
• tandemová hmotnostní spektrometrie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• catechol MeSH Prohlížeč
• estrogeny MeSH
• katechol-O-methyltransferasa * MeSH
• katecholestrogeny MeSH
• katecholy MeSH
• receptory pro estrogeny MeSH