Prognostic value of integrin αV expression and localization pattern in invasive breast carcinomas

Cerqueira, Otto Luiz Dutra; Botelho, Mayara Carolline Silva; Fiore, Ana Paula Zen Petisco; Osório, Cynthia Aparecida Bueno de Toledo; Tomasin, Rebeka; Morais, Mauro César Cafundó de; López, Rossana Verónica Mendoza; Cardoso, Elizabeth; Vilella-Arias, Santiago A.; Reis, Eduardo M.; Bruni‐Cardoso, Alexandre

doi:10.1016/j.neo.2022.100803

Cited by 6 publications

(12 citation statements)

References 71 publications

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“…MCL1 inhibition by 10 µM A-1210477 markedly reduced β1 and β3 subunit expression while the levels of αν were highly increased, a data point that is particularly interesting. In fact, it was reported that integrin αν has some peculiarities with respect to other integrins because it can dimerize with five different β subunits, forming heterodimers that recognize different ECM ligands and appearing as an important target for the development of therapeutic cancer strategies [ 77 ].…”

Section: Discussionmentioning

confidence: 99%

MCL1 Inhibition Overcomes the Aggressiveness Features of Triple-Negative Breast Cancer MDA-MB-231 Cells

Pratelli

Carlisi

Liberto

et al. 2023

IJMS

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Triple-Negative Breast Cancer (TNBC) is a particularly aggressive subtype among breast cancers (BCs), characterized by anoikis resistance, high invasiveness, and metastatic potential as well as Epithelial–Mesenchymal Transition (EMT) and stemness features. In the last few years, our research focused on the function of MCL1, an antiapoptotic protein frequently deregulated in TNBC. Here, we demonstrate that MCL1 inhibition by A-1210477, a specific BH3-mimetic, promotes anoikis/apoptosis in the MDA-MB-231 cell line, as shown via an increase in proapoptotic markers and caspase activation. Our evidence also shows A-1210477 effects on Focal Adhesions (FAs) impairing the integrin trim and survival signaling pathways, such as FAK, AKT, ERK, NF-κB, and GSK3β-inducing anoikis, thus suggesting a putative role of MCL1 in regulation of FA dynamics. Interestingly, in accordance with these results, we observed a reduction in migratory and invasiveness capabilities as confirmed by a decrease in metalloproteinases (MMPs) levels following A-1210477 treatment. Moreover, MCL1 inhibition promotes a reduction in EMT characteristics as demonstrated by the downregulation of Vimentin, MUC1, DNMT1, and a surprising re-expression of E-Cadherin, suggesting a possible mesenchymal-like phenotype reversion. In addition, we also observed the downregulation of stemness makers such as OCT3/4, SOX2, NANOG, as well as CD133, EpCAM, and CD49f. Our findings support the idea that MCL1 inhibition in MDA-MB-231 could be crucial to reduce anoikis resistance, aggressiveness, and metastatic potential and to minimize EMT and stemness features that distinguish TNBC.

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Section: Discussionmentioning

confidence: 99%

MCL1 Inhibition Overcomes the Aggressiveness Features of Triple-Negative Breast Cancer MDA-MB-231 Cells

Pratelli

Carlisi

Liberto

et al. 2023

IJMS

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“…The Hippo pathway and YAP have been implicated in the development of diseases, particularly cancer and conditions of disrupted tissue regeneration, and one of the hallmarks of adenocarcinomas is the disruption of the basement membrane along with loss of epithelia polarity and proliferative quiescence (Cerqueira et al, 2022; Fiore et al, 2017; Tomasin et al, 2023; Zhao, Li, Lei, et al, 2010). Our findings that human breast malignant cells (T4-2 cells) in 3-rBM presents elevated concentrations of nuclear YAP suggests that the highly proliferative capacity of malignant cells, even in a growth-suppressive environment like that provided by basement membrane components, might be linked with deregulated YAP, both in the nucleus and in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…Chemical and mechanical signals provided by the extracellular (ECM) regulate a milieu of cellular processes. Reciprocally, cells remodel the ECM by differentially secreting and/or degrading ECM molecules and by altering the ECM topology (Cerqueira et al, 2022; Walma & Yamada, 2020). This complex molecular interplay, involving bidirectional communication between the extracellular matrix (ECM) and cells, plays a critical role in tissue development, homeostasis, and proper function, and is disrupted in diseases such as cancer (Fiore et al, 2018; Walma & Yamada, 2020).…”

Section: Introductionmentioning

confidence: 99%

The basement membrane regulates the cellular localization and the cytoplasmic interactome of Yes-Associated Protein (YAP) in mammary epithelial cells

Manucci,

Fiore,

Genesi

et al. 2023

Preprint

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Extracellular matrix (ECM) signals play a pivotal role in shaping the fate and behavior of epithelial cells within the mammary gland. However, we still lack detailed knowledge on the mechanisms underlying these processes. The Hippo pathway, a signaling cascade involved in the regulation of organ size and several other processes, acts as a conduit between ECM cues and cellular responses. We asked whether the basement membrane (BM), a specialized ECM component known to induce quiescence and differentiation in mammary epithelial cells, would regulate the localization, activity and interactome of YAP, a Hippo pathway effector. Our exploration encompassed a range of experimental contexts, including 2D and 3D cultures of both mouse and human mammary epithelial cells, as well as the developing mouse mammary gland. In contrast to malignant cells, non-tumoral cells cultured with a reconstituted BM (rBM) displayed higher concentrations of YAP in the cytoplasm. Incidentally, when in the nucleus of rBM-treated cells, YAP resided preferentially at the nuclear periphery. Notably, in agreement with our cell culture experiments, YAP exhibited cytoplasmic predominance in ductal cells of developing mammary epithelia, where a denser BM envelops the cells. Conversely, terminal end bud (TEB) cells with a thinner BM displayed higher nucleus-to-cytoplasm ratios of YAP. Bioinformatic analysis revealed that genes regulated by YAP were overrepresented in the transcriptomes of microdissected TEBs. Consistently, mouse epithelial cells exposed to the rBM expressed lower levels of YAP-regulated genes, although the level of YAP and Hippo components were not altered by the treatment. Mass spectrometry analysis identified a differential set of proteins interacting with YAP in cytoplasmic fractions of mouse epithelial cells in the absence or presence of rBM. In untreated cells, YAP interactants were enriched in processes related to ubiquitin-mediated proteolysis, whereas in cells exposed to rBM YAP interactants were mainly key proteins related to amino acid, amino sugar and carbohydrate metabolism. Collectively, our multifaceted approach unraveled that the BM induces YAP translocation or retention in the cytoplasm of non-tumoral epithelial cells and that in the cytoplasm YAP seems to undertake novel functions in metabolic pathways.

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“…Similar patterns of association with prognosis have been reported for the Integral Membrane Protein 2A tumor suppressor gene ITM2A [21] and for the gene encoding for the myosin heavy chain 11 (MYH11 ). which has been linked to better clinical outcomes in terms of both overall and disease-free survival in breast cancer [22]. In addition, the loss of constitutive ABCB1 expression, one of the top up-regulated genes in node 2, has been linked to worse prognosis in breast cancer patients [23] and breast cancer patients with high expression levels of AQP1 treated with anthracyclines are known to display better clinical outcomes relative to those with low AQP1 levels [24].…”

Section: Discussionmentioning

confidence: 99%

Progression Analysis of Disease with Survival (PAD-S) by SurvMap identifies different prognostic subgroups of breast cancer in a large combined set of transcriptomics and methylation studies

Forés-Martos

Suay-García

Bosch-Romeu

et al. 2022

Preprint

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Progression analysis of disease (PAD) is a methodology that incorporates the output of Disease Specific Genomic Analyses (DSGA) to an unsupervised classification scheme based on Topological Data Analysis (TDA). PAD makes use of data derived from healthy individuals to split individual diseased samples into healthy and disease components. Then, the shape characteristics of the disease component are extracted trough the generation of a combinatioral graph by means of the Mapper algorithm. In this paper we introduce a new filtering function for the Mapper algorithm that naturally integrates information on genes linked to disease-free or overall survival. We propose a new PAD9 extended methodology termed Progression Analysis of Disease with Survival (PAD-S) and implement it in an R package called SurvMap which allows users to carry out all the steps involved in PAD11 S, as well as in traditional PAD analyses. We tested PAD-S methodology using SurvMap on a large combined transcriptomics breast cancer dataset demonstrating its capacity to identify sets of samples displaying highly significant differences in terms of disease free survival (p = 8 x 10−14) and idiosyncratic biological features. PAD-S and SurvMap were also able to identify sets of samples with significantly different relapse-free survivals and molecular profiles inside breast cancer intrinsic subgroups (luminal A, luminal B, Her2, and basal). Finally, to illustrate that PAD-S and SurvMap are general-purpose analysis tools that can be applied to different types of omics data, we also carried out analyses in a breast cancer methylation dataset derived from The Cancer Genome Atlas (TCGA) identifying groups of patients with significant differences in terms of overall survival and methylation profiles.

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Prognostic value of integrin αV expression and localization pattern in invasive breast carcinomas

Cited by 6 publications

References 71 publications

MCL1 Inhibition Overcomes the Aggressiveness Features of Triple-Negative Breast Cancer MDA-MB-231 Cells

MCL1 Inhibition Overcomes the Aggressiveness Features of Triple-Negative Breast Cancer MDA-MB-231 Cells

The basement membrane regulates the cellular localization and the cytoplasmic interactome of Yes-Associated Protein (YAP) in mammary epithelial cells

Progression Analysis of Disease with Survival (PAD-S) by SurvMap identifies different prognostic subgroups of breast cancer in a large combined set of transcriptomics and methylation studies

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