The expression pattern of MUC1 (EMA) is related to tumour characteristics and clinical outcome of invasive ductal breast carcinoma

Aims: To clarify MUC1 patterns in invasive ductal breast carcinoma and to relate them to clinicopathological parameters, coexpression of other biological markers and prognosis. Methods and results: Samples from 243 consecutive patients with primary ductal carcinoma were incorporated into tissue microarrays (TMAs). Slides were stained for MUC1, oestrogen receptor (ER), progesterone receptor (PR), Her2/neu, p53 and cyclin D1. Apical membrane MUC1 expression was associated with smaller tumours (P = 0.001), lower tumour grades (P < 0.001), PR positivity (P = 0.003) and increased overall survival (OS; P = 0.030). Diffuse cytoplasmic MUC1 expression was associated with cyclin D1 positivity (P = 0.009) and increased relapse-free survival (RFS; P = 0.034). Negativity for MUC1 was associated with ER negativity (P = 0.004), PR negativity (P = 0.001) and cyclin D1 negativity (P = 0.009). In stepwise multivariate analysis MUC1 negativity was an independent predictor of both RFS [hazard ratio (HR) 3.5, 95% confidence interval (CI) 1.5, 8.5; P = 0.005] and OS (HR 14.7, 9 5% Cl 4.9, 44. 1; P < 0.001). Conclusions: The expression pattern of MUC1 in invasive ductal breast carcinoma is related to tumour characteristics and clinical outcome. In addition, negative MUC1 expression is an independent risk factor for poor RFS and OS, besides 'classical' prognostic indicators

Glycosylation pattern of brush border-associated glycoproteins in enterocyte-like cells: involvement of complex-type N-glycans in apical trafficking

We have previously reported that galectin-4, a tandem repeat-type galectin, regulates the raft-dependent delivery of glycoproteins to the apical brush border membrane of enterocyte-like HT-29 cells. N-Acetyllactosamine-containing glycans, known as galectin ligands, were found enriched in detergent-resistant membranes. Here, we analyzed the potential contribution of N-and/ or O-glycans in this mechanism. Structural studies were carried out on the brush border membrane-enriched fraction using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and nano-ESI-QTOF-MS/MS. The pattern of N-glycans was very heterogeneous, with the presence of high mannose- and hybrid-type glycans as well as a multitude of complex-type glycans. In contrast, the pattern of O-glycans was very simple with the presence of two major core type 1 O-glycans, sialylated and bisialylated T-antigen structures {[}Neu5Ac alpha 2-3Gal beta 1-3GalNAc-ol and Neu5Ac alpha 2-3Gal beta 1 -3(Neu5Ac alpha 2-6)GalNAc-ol]. Thus, N-glycans rather than O-glycans contain the N-acetyllactosamine recognition signals for the lipid raft-based galectin-4-dependent apical delivery. In the presence of 1-deoxymannojirimycin, a drug which inhibits the generation of hybrid-type or complex type N-glycans, the extensively O-glycosylated mucin-like MUC1 glycoprotein was not delivered to the apical brush border but accumulated inside the cells. Altogether, our data demonstrate the crucial role of complex N-glycans in the galectin-4-dependent delivery of glycoproteins to the apical brush border membrane of enterocytic HT-29 cells

Tissue-specific expression of a human Polymorphic Epithelial mucin (MUCI) in transgenic mice

The human MUC1 gene codes for the core protein of a mucin which is expressed by glandular epithelia and the carcinomas which develop from these tissues. The core protein is aberrantly glycosylated in cancers, and some antibodies show specificity in their reactions with the cancer-associated mucin, which also contains epitopes recognized by T-cells from breast and pancreatic cancer patients. For evaluating the potential use of mucin-reactive antibodies and mucin-based immunogens in cancer patients, a mouse model, expressing the MUC1 gene product PEM (polymorphic epithelial mucin) as a self antigen, would be extremely useful. To this end, we have developed transgenic mouse strains expressing the human MUC1 gene product in a tissue-specific manner. The TG4 mouse strain was established using a 40-kilobase fragment containing 4.5 kilobases of 5\u27 and 27 kilobases of 3\u27 flanking sequence. The TG18 strain was developed using a 10.6-kilobase SacII fragment from the 40-kilobase fragment; this fragment contained 1.6 kilobases of 5\u27 sequence and 1.9 kilobases of 3\u27 flanking sequence. Both strains showed tissue specificity of expression of the MUC1 gene, which was very similar to the profile of expression seen in human tissues. The antibody SM-3 is directed to a core protein epitope, which is selectively exposed in breast cancers and which shows a more restricted distribution on normal human tissues. It was established that the distribution of the SM-3 epitope of PEM in the tissues of the transgenic mice is similar to that seen in humans. The transgenic mouse strains described here should form the basis for the development of a preclinical model for the evaluation of PEM-based antigens and of antibodies directed to PEM in cancer therapy

Intention and motor representation in purposive action

Are there distinct roles for intention and motor representation in explaining the purposiveness of action? Standard accounts of action assign a role to intention but are silent on motor representation. The temptation is to suppose that nothing need be said here because motor representation is either only an enabling condition for purposive action or else merely a variety of intention. This paper provides reasons for resisting that temptation. Some motor representations, like intentions, coordinate actions in virtue of representing outcomes; but, unlike intentions, motor representations cannot feature as premises or conclusions in practical reasoning. This implies that motor representation has a distinctive role in explaining the purposiveness of action. It also gives rise to a problem: were the roles of intention and motor representation entirely independent, this would impair effective action. It is therefore necessary to explain how intentions interlock with motor representations. The solution, we argue, is to recognise that the contents of intentions can be partially determined by the contents of motor representations. Understanding this content-determining relation enables better understanding how intentions relate to actions

The MUC1 Cytoplasmic Tail and Tandem Repeat Domains Contribute to Mammary Oncogenesis in FVB Mice

Background: Though the importance of the transmembrane mucin MUC1 in mammary oncogenesis has long been recognized, the relative contributions of the cytoplasmic tail and tandem repeat domains are poorly understood.Methods: To address this, mouse models of mammary carcinogenesis were created expressing full-length, cytoplasmic tail-deleted, or tandem repeat-deleted MUC1 constructs.Results: Overexpression of full-length MUC1 resulted in tumor formation in young mice (12 months); however, loss of either the cytoplasmic tail or the tandem repeat domain abrogated this oncogenic capacity. Aged mice in all strains developed late-onset mammary tumors similar to those previously described for the FVB background.Conclusions: This study is the fi rst spontaneous cancer model to address the relative importance of the cytoplasmic tail and tandem repeat domains to MUC1-driven mammary oncogenesis, and suggests that both of these domains are essential for tumor formation

#8M Paro internacional de mujeres : Reflexiones en torno a la apropiación feminista de TIC

Tras un proceso intenso de organización y coordinación favorecido por tecnologías digitales, el 8 de marzo de 2017 se gestó un acontecimiento inédito en la historia feminista, el primer Paro Internacional de Mujeres con adhesión de 57 países, que contó con destacada participación en Latinoamérica. Este gesto político disruptivo suele ser invocado desde metáforas tales como: «marea feminista», «movimiento que hizo temblar la tierra» y «un tsunami de mujeres». La conmemoración del 8 de marzo como Día Internacional de las Mujeres cuenta con una vasta trayectoria en el activismo de organizaciones de mujeres y feministas del mundo, y adquirió renovado impulso a fines de los ’60 en el contexto de la segunda ola feminista de países del norte; mientras que en países latinoamericanos, en particular del cono sur, las acciones colectivas se retomaron en los años ’80, con la recuperación democrática. Desde entonces, de modo paulatino el 8 de marzo se instituyó como fecha clave del activismo de mujeres y feminista a nivel mundial, tanto como espacio de resistencia a la cooptación propiciada por el consumismo capitalista como ocasión para el agasajo de féminas.Facultad de Humanidades y Ciencias de la EducaciónInstituto de Investigaciones en Humanidades y Ciencias Sociale

Genetic regulation of MUC1 alternative splicing in human tissues

The membrane mucin MUC1 is aberrantly expressed in a variety of cancers, and in stomach, it is a ligand for Helicobacter pylori where it plays a role in gastric carcinogenesis. Splicing variation, leading to a 9-amino acid insertion in the signal peptide region, was proposed to be because of a single-nucleotide polymorphism (rs4072037) at the 5′ end of exon 2, but is also reported to be cancer-associated. However, the effect of rs4072037 on this splicing event in healthy non-cancer tissues and on the additional spliceoforms of MUC1, including those lacking the polymorphic tandem repeat (TR) domain, has never been investigated. Here we show that in both foetal and adult tissues of known genotype, there is clear evidence for the role of rs4072037 in controlling alternative splicing of the 5′ exon 2 region of both full-length transcripts and those lacking the TR domain. Although there is some evidence for additional genetic and epigenetic influences, there is no indication of an effect of the TR domain on the proportions of the spliceoforms. In conclusion, over-representation of certain transcripts in tumour material cannot be evaluated without information on the SNP genotype as well