Molecular basis of anti-hormonal treatment and resistance in breast cancer

Le cancer du sein est le plus fréquent cancer chez les femmes dans le monde. Environ 70% des tumeurs mammaires expriment le récepteur des oestrogènes alpha (REa) et sont considérées comme hormono-sensibles. La thérapie hormonale a longtemps été le traitement de choix. Toutefois, les effets agonistes sur le REa et le développement de la résistance des thérapies actuels, tels que le tamoxifène nécessitent le développement de nouveaux traitements qui agissent par des mécanismes distincts. L'objectif de notre étude était de concevoir des outils qui peuvent aider à comprendre les mécanismes moléculaires impliqués dans la modulation ligand-dépendante ou dans la dégradation du REa. Nous avons choisi quelques anti-oestrogènes avec différentes structures et nous avons comparé leurs effets sur: 1. la dégradation du REa.2. La localisation intra-cellulaire du REa. 3. La régulation de la transcription des gènes cibles du REa 4. La régulation de la transcription dans les mutants de REa. Grace à notre appproche mécanistique, nous avons pu classer ces anti-estrogènes en trois groupes sur la base de leur fonction : SERM, SERD et un nouveau groupe EM. Les SERM (selective estrogen receptor modulator) stabilisent le REa, induisent une re-localisation du REa dans le noyau, augmentent l'activité transcriptionnelle de mutants qui affectent le recrutement de cofacteurs et qui altèrent la liaison avec la chaîne latérale de l'anti-œstrogène et, enfin, manquent de pouvoir d'inhibition de l'expression basale de gènes endogènes. Les SERD (selective estrogen receptor disruptor) induisent une dégradation protéasome dépendante du REa dans le noyau en formation des foyers nucléaires qui colocalisent avec le proteasome, et inhibent l'expression basale du gène endogène du récepteur de la progestérone (PGR). Enfin, EM652 est un composé qui affecte le devenir du RE comme les SERM mais qui a un effet inhibiteur sur l'expression basale du gene endogene PGR. Cette approche peut être utilisée pour cribler de nouveaux anti-oestrogènesBreast cancer is the most common type of malignancy among women in the world. Approximately 70% of breast tumours express the estrogen receptor alpha (ERa) and are considered hormone-responsive. Endocrine therapies have long been the treatment of choice. However, the estrogen- like agonist effect and development of resistance of the available selective estrogen receptor modulator such as tamoxifen require developing new treatments that act through different mechanisms. The objective of our study is to design tools that can help to understand the molecular mechanisms involved in ligand-dependent modulation or degradation of ERa. We selected a set of anti-estrogens with different structures and compared their effect on: 1. ERa degradation. 2. Intra-cellular localisation of ERa. 3. Regulation of transcription of ERa- endogenous target genes. 4. Regulation of transcription in the mutants of ERa. Using this mechanistic study we could classify the tested anti-estrogens into three groups based on their function: SERM, SERD and a new group for EM652. SERM (selective estrogen receptor modulator) include compounds such as OH-tamoxifen and RU39411, that stabilise ERa, that re-localize ERa into the nucleus upon binding, that increase transcriptional activity in mutants affecting the recruitment of cofactors or the binding of their side chain and that lack inhibitory capacities of the basal expression of endogenous genes. SERD (selective estrogen receptor modulator) include compounds such as ICI182580 or RU58668, that induce nuclear proteasome-dependent degradation ERalpha which occur in large nuclear foci that colocalize with the proteasome and that inhibit basal gene expression of the endogenous progesterone receptor gene (PGR). Finally, EM652 was found to affect ER degradation and localisation similarly to SERM but inhibited basal gene expression of the endogenous PG

EGFR expression evaluation in esophageal cancer patients

Background and aims: Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer death worldwide. In Iran, esophageal cancer is the second and third most common cancer in the men and women, respectively. The epidermal growth factor receptor (EGFR) is a receptor of tyrosine kinase from the ErbB family, with its disorder in the pathophysiology of many epithelial malignancies, including esophageal cancer, and is the important agent in prognosis and clinical progression of the disease. In this research project, the EGFR expression was investigated in Iranian patients with esophageal cancer using the qRT-PCR. Methods: This research was a cohort historical study. Thirty paraffin-embedded tissue samples of normal esophageal and cancer tissues were analyzed to measure the EGFR expression. PCR reactions for EGFR and β-actin were carried out by Livac method. All data were analyzed by SPSS software. Results: The results showed a significant difference between the EGFR expression in patients compared to control group (P<0.05). The EGFR overexpression in patients was 4.25 times higher compared to healthy group. Conclusion: EGFR increased in the patients compared to the control group, which may be used as a potential biomarker for esophageal cancer in the Iranian population

Antibacterial activity of Marrubium vulgare L. against antibiotic resistance Klebsiella pneumoniae strains

Background and aims: Herbal medicines are the major remedy in traditional medical systems and have a great contribution in maintaining human health and preventing many infectious diseases. The aim of this study was to assay antibacterial potential of Marrubium vulgare L. extract against Klebsiella pneumoniae resistant strains to current antibiotics and also GC/MS analysis to better understanding the extract composition. Methods: In this experimental research, 30 K. pneumoniae strains isolated from urine culture of hospitalized patients were used. The essential oil of Marrubium vulgare L. was obtained by hydro distillation for 2 hours using the Celevenger with yield of 75. Methanolic extract from M. vulgare L. was prepared using Rotary apparatus. In order to determine chemical composition of essential oil, gas chromatography coupled with mass spectrometry (GC-MS) was performed. The minimum inhibitory concentrations and minimum bacterial concentrations were investigated to characterize the antimicrobial activities of this essential oil and its extract. Data were analyzed using analysis of variance (one-way) to determine the statistical differences between different tests. Results: The results showed that K. pneumoniae strains were resistant to 4 or 3 agents including: Ampicillin (65), Gentamicin (30), Sulfamethoxazol (25). The lowest and the highest MIC value of M. vulgare L. extract were 2.5 and 10 mg/mL, respectively. The highest and the lowest MIC value of M. vulgare L. essential oil was 5 and 1/25 mg/m respectively. Conclusion: The present study confirmed that essential oil and extract of this plant could be served as an antibacterial agent in pharmaceutical industry

Case Report: Mutation in AIMP2/P38, the Scaffold for the Multi-Trna Synthetase Complex, and Association With Progressive Neurodevelopmental Disorders

Background: Leukodystrophies constitute a heterogeneous group of inherited disorders primarily affecting the white matter of the central nervous system. Aminoacyl-tRNA synthetases (ARSs) catalyze the attachment of an amino acids to their cognate transfer RNAs (tRNAs). Pathogenic variants in both cytosolic and mitochondrial ARSs have been linked to a broad range of neurological disorders, including hypomyelinating leukodystrophies and pontocerebellar hypoplasias (PCH). Aminoacyl tRNA synthetase-interacting multifunctional protein 2 (AIMP2), one of the three non-catalytic components of multi ARS complex, harbors anti-proliferative activity and functions as a proapoptotic factor thus promoting cell death. We report a case of a 7-month-old infant with a complex clinical presentation, including weight loss, severe anemia, skeletal abnormalities, microcephaly and MR imaging features of leukodystrophy with a novel mutation in AIMP2. Methods: Whole-exome sequencing (WES) was performed on the proband. Parental samples were analyzed by PCR amplification and Sanger sequencing. Results: Whole-exome sequencing revealed a novel variant c.A463T in the homozygous state in exon 3 (NM_001,326,607) of AIMP2 [p.(K155X)] in the proband. Parental carrier status was confirmed by target sequencing. Conclusion: Here, we present an Iranian case with leukodystrophy with a novel AIMP2 mutation. This finding broadens the mutational and phenotypic spectra of AIMP2-related leukodystrophy and offers guidance for proper genetic counselling for pre- and post-natal screenings as well as for disease management

The Combination of Molecular Aspects of Breast Cancer with Hormone Therapy

Background &amp; Objectives: Breast cancer is one of the most common cancers in the world that is affected by various genetics, epigenetic and many other environmental factors. Estrogen is one of the risk factors for this cancer. This factor lead to genetic alterations and the beginning and promotion of breast cancer. Materials &amp; Methods: In this review, we provide information using databases of NCBI, PubMed, Google Scholar, and Ovid MEDLINE, about the molecular basis of breast cancer, the effect of estrogen hormone, and estrogen receptors on cancer incidence, the use of anti-estrogens such as Tamoxifen in treatment of breast cancer and mechanisms of resistant to these drugs. Result: Anti-estrogens such as tamoxifen play an important role in treatment of estrogen-receptor positive breast cancers by preventing estrogen binding to its receptors in these tumors. Finding the molecular basis of breast cancer will help us to achieve effective treatment for breast cancer. Conclusion: Increased estrogen and estrogen receptor highly influence the incidence of breast cancer. Tamoxifen is standard adjuvant therapy for women with ER-positive +, but there is some intrinsic or acquired resistance to endocrine treatment that require further investigations.

Ligands specify estrogen receptor alpha nuclear localization and degradation

Abstract Background The estrogen receptor alpha (ERα) is found predominately in the nucleus, both in hormone stimulated and untreated cells. Intracellular distribution of the ERα changes in the presence of agonists but the impact of different antiestrogens on the fate of ERα is a matter of debate. Results A MCF-7 cell line stably expressing GFP-tagged human ERα (SK19 cell line) was created to examine the localization of ligand-bound GFP-ERα. We combined digitonin-based cell fractionation analyses with fluorescence and immuno-electron microscopy to determine the intracellular distribution of ligand-bound ERα and/or GFP-ERα. Using fluorescence- and electron microscopy we demonstrate that both endogenous ERα and GFP-ERα form numerous nuclear focal accumulations upon addition of agonist, 17β-estradiol (E2), and pure antagonists (selective estrogen regulator disruptor; SERD), ICI 182,780 or RU58,668, while in the presence of partial antagonists (selective estrogen regulator modulator; SERM), 4-hydroxytamoxifen (OHT) or RU39,411, diffuse nuclear staining persisted. Digitonin based cell fractionation analyses confirmed that endogenous ERα and GFP-ERα predominantly reside in the nuclear fraction. Overall ERα protein levels were reduced after estradiol treatment. In the presence of SERMs ERα was stabilized in the nuclear soluble fraction, while in the presence of SERDs protein levels decreased drastically and the remaining ERα was largely found in a nuclear insoluble fraction. mRNA levels of ESR1 were reduced compared to untreated cells in the presence of all ligands tested, including E2. E2 and SERDs induced ERα degradation occurred in distinct nuclear foci composed of ERα and the proteasome providing a simple explanation for ERα sequestration in the nucleus. Conclusions Our results indicate that chemical structure of ligands directly affect the nuclear fate and protein turnover of the estrogen receptor alpha independently of their impact on transcription. These findings provide a molecular basis for the selection of antiestrogen compounds issue from pharmacological studies aimed at improving treatment of breast cancer.</p

Synthesis, in vitro and cellular antioxidant activity evaluation of novel peptides derived from Saccharomyces cerevisiae protein hydrolysate : structure-function relationship

The relationship between structure and function of primary antioxidant peptide, YR-10 (YGKPVAVPAR) was considered by synthesizing three analogues including YHR-10 (YGKHVAVHAR), GA-8 (GKPVAVPA) and PAR-3 (PAR). Antioxidant activity was determined through in vitro and cellular assays. Substitution of Pro with His in the structure of YR-10 led to significant (P < 0.05) higher ABTS radical scavenging and ferric reducing activity. Following in silico simulated gastrointestinal digestion, Tyr and Arg were omitted, respectively, from N and C-terminal positions and resulted in decreasing DPPH, ABTS radical scavenging, and ferric reducing activities. PAR-3 showed the best inhibitory activity on linoleic acid oxidation. Pretreatment of Caco-2 cells with YR-10, YHR-10, and GA-8 (1000 mu M) before exposure to H2O2 (160 mu M) resulted in 34.10%, 39.66% and 29.159% reduction in malondialdehyde and 53.52%, 17.02% and 24.71% reduction in protein carbonyl levels. The peptide pretreatment reduced catalase level in cells and PAR-3 exhibited the most protective effects on the viability of cells exposed to oxidative stress

Association between the p53 codon 72 polymorphism and primary open-angle glaucoma risk: Meta-analysis based on 11 case–control studies

The TP53 is important in functions of cell cycle control, apoptosis, and maintenance of DNA integrity. Studies on the association between p53 codon 72 polymorphism and primary open-angle glaucoma (POAG) risk have yielded conflicting results. Published literature from PubMed and Web of Science databases was retrieved. All studies evaluating the association between p53 codon 72 polymorphisms and POAG were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated. Eleven separate studies including 2541 cases and 1844 controls were pooled in the meta-analysis. We did not detect a significant association between POAG risk and p53 codon 72 polymorphism overall population except allele genetic model (C vs. G: OR = 0.961, 95% CI = 0.961–0.820, P = 0.622). In the stratified analysis for Asians and Caucasians, there was an association between p53 codon 72 polymorphism and POAG. In the dominant model in the overall population and by ethnicity subgroups, the highest elevated POAG risk was presented. In summary, these results indicate that p53 codon 72 polymorphism is likely an important genetic factor contributing to susceptibility of POAG. However, more case–controls studies based on larger sample size and stratified by ethnicity are suggested to further clarify the relationship between p53 codon 72 polymorphism and POAG