Miguel Ángel Velázquez-Flores

Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (review).

Anti-estrogens such as tamoxifen are widely used in the clinic to treat estrogen receptor-positive breast tumors. Patients with estrogen receptor-positive breast cancer initially respond to treatment with anti-hormonal agents such as tamoxifen, but remissions are often followed by the acquisition of resistance and, ultimately, disease relapse. The development of a rationale for the effective treatment of tamoxifen-resistant breast cancer requires an understanding of the complex signal transduction mechanisms. In the present study, we explored some mechanisms associated with resistance to tamoxifen, such as pharmacologic mechanisms, loss or modification in estrogen receptor expression, alterations in co-regulatory proteins and the regulation of the different signaling pathways that participate in different cellular processes such as survival, proliferation, stress, cell cycle, inhibition of apoptosis regulated by the Bcl-2 family, autophagy, altered expression of microRNA, and signaling pathways that regulate the epithelial-mesenchymal transition in the tumor microenvironment. Delineation of the molecular mechanisms underlying the development of resistance may aid in the development of treatment strategies to enhance response and compromise resistance.

A proteomic approach of pediatric astrocytomas: MiRNAs and network insight.

UNLABELLED Pediatric astrocytomas, a leading cause of death associated with cancer, are the most common primary central nervous system tumors found in children. Most studies of these tumors focus on adults, not on children. We examined the global protein and microRNA expression pattern by 2D SDS-PAGE, mass spectrometry (MALDI-TOF), and RT(2) miRNA PCR Array System. Proteomic studies revealed 49 proteins with changes on the expression. Interactome showed that vimentin, calreticulin, and 14-3-3 epsilon protein are hub proteins in these neoplasms. MicroRNA analyses demonstrated for the first time novel microRNAs involved in the astrocytoma biology. In conclusion, our results show that novel proteins and microRNAs with expression changes on pediatric astrocytoma could serve as biomarkers of tumor progression. BIOLOGICAL SIGNIFICANCE Astrocytomas are tumors that progress rapidly and that invade surrounding tissues. Although some drugs have been developed to treat these neoplasms, the mortality of patients is still very high. In this study, we describe for the first time, to our knowledge, some proteins and miRNAs associated with the biology of astrocytic tumors that could be postulated as possible diagnostic or prognostic biomarkers. Altogether, our results indicate that large-scale analyses allow making a fairly accurate prediction of different cellular processes altered in astrocytic tumors.

Duplication of the Miller-Dieker Critical Region in a Patient with a Subtelomeric Unbalanced Translocation t(10;17)(p15.3;p13.3)

Submicroscopic duplications in the Miller-Dieker critical region have been recently described as new genomic disorders. To date, only a few cases have been reported with overlapping 17p13.3 duplications in this region. Also, small deletions that affect chromosome region 10p14→pter are rarely described in the literature. In this study, we describe, to our knowledge for the first time, a 5-year-old female patient with intellectual disability who has an unbalanced 10;17 translocation inherited from the father. The girl was diagnosed by subtelomeric FISH and array-CGH, showing a 4.43-Mb heterozygous deletion on chromosome 10p that involved 14 genes and a 3.22-Mb single-copy gain on chromosome 17p, which includes the critical region of the Miller-Dieker syndrome and 61 genes. The patient’s karyotype was established as 46,XX.arr 10p15.3p15.1(138,206–4,574,436)x1,17p13.3(87,009–3,312,600)x3. Because our patient exhibits a combination of 2 imbalances, she has phenotypic features of both chromosome abnormalities, which have been reported separately. Interestingly, the majority of patients who carry the deletion 10p have visual and auditory deficiencies that are attributed to loss of the GATA3 gene. However, our patient also presents severe hearing and visual problems even though GATA3 is present, suggesting the involvement of different genes that affect the development of the visual and auditory systems.

Glycine receptor subunits expression in the developing rat retina

Background and methods: Glycine receptor (GlyR) consists of two &agr; (1–4) and three &bgr; subunits. Considerable evidence indicates that the adult retina expresses the four types of &agr; subunits; however, the proportion of these subunits in adult and immature retina is almost unknown. In this report we have studied mRNA and the protein expression of GlyR subunits in the retina during postnatal rat development by Real‐Time qRT‐PCR and western blot. Results: mRNA and protein expression indicated a gradual increase of the &agr;1, &agr;3, &agr;4 and &bgr; GlyR subunits during postnatal ages tested. The mRNA &bgr; subunit showed higher expression levels (˜3 fold) than those observed for the &agr;1 and &agr;3 subunits. Very interestingly, the &agr;2 GlyR subunit had the highest expression in the retina, even in the adult. Conclusions: These results revealed the expression of GlyR at early postnatal ages, supporting its role in retina development. In addition, our results indicated that the adult retina expressed a high proportion of the &agr;2 subunit, suggesting the expression of monomeric and/or heteromeric receptors. A variety of studies are needed to further characterize the role of the specific subunits in both adult and immature retina. HighlightsGlycine receptor &agr;1 and &agr;2 are the main subunits in the adult rat retina.GlyR &agr;2 subunit remains almost constant during postnatal development in rat retina.The high proportion of &agr;2 subunit, suggests monomeric and/or heteromeric receptors.GlyR signals may be involved in developmental and differentiation pathways.

Differentially Expressed Long Non-Coding RNAs Were Predicted to Be Involved in the Control of Signaling Pathways in Pediatric Astrocytoma

Expression changes for long non-coding RNAs (lncRNAs) have been identified in adult glioblastoma multiforme (GBM) and in a mixture of adult and pediatric astrocytoma. Since adult and pediatric astrocytomas are molecularly different, the mixture of both could mask specific features in each. We determined the global expression patterns of lncRNAs and messenger RNA (mRNAs) in pediatric astrocytoma of different histological grades. Transcript expression changes were determined with an HTA 2.0 array. lncRNA interactions with microRNAs and mRNAs were predicted by using an algorithm and the LncTar tool, respectively. Interactomes were constructed with the HIPPIE database and visualized with the Cytoscape platform. The array showed expression changes in 156 and 207 lncRNAs in tumors (versus the control) and in pediatric GBM (versus low-grade astrocytoma), respectively. Predictions identified lncRNAs that have putative microRNA binding sites, which might suggest that they function as sponges in these tumors. Also, lncRNAs were shown to interact with many mRNAs, such as Pleckstrin homology-like domain, family A, member 1 (PHLDA1) and sulfatase 2 (SULF2). For example, qPCR found long intergenic non-coding RNA regulator of reprogramming (linc-RoR) expression levels upregulated in pediatric GBM when they were compared with control tissues or with low-grade tumors. Meanwhile, PHLDA1 and ELAV-like RNA binding protein 1 (ELAV1) showed expression changes in tumors relative to the control. Our data showed many lncRNAs with expression changes in pediatric astrocytoma, which might be involved in the regulation of different signaling pathways.

Clinical and Molecular Characterization of a Patient with 15q21.2q22.2 Deletion Syndrome

We report on a 16-year-old girl with a complex phenotype, including intellectual disability, facial dysmorphisms, and obesity. During her infancy, she presented with weak sucking, global developmental delay, and later with excessive eating with central obesity. The girl was clinically diagnosed with probable Prader-Willi syndrome. Chromosomal analysis showed a de novo deletion 46,XX,del(15)(q21q22). However, the use of the Affymetrix CytoScan HD Array defined the exact breakpoints of the deleted 15q21q22 region. The imbalance, about 10.5 Mb in size, is to date the second largest deletion ever described in this chromosomal region. In addition, our patient carries a microdeletion in the 1q44 region and a gain in 9p24. The array result was arr[hg19] 9p24.1(6,619,823-6,749,335)×3, 1q44(248,688,586-248,795,277)×1, 15q21.2 q22.2(50,848,301-61,298,006)×1. Although our patient presents additional chromosomal alterations, we provide a correlation between the clinical findings and the phenotype of the 15q21 deletion syndrome.