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1.
Cell ; 159(6): 1461-75, 2014 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-25433701

RESUMEN

Identifying driver genes in cancer remains a crucial bottleneck in therapeutic development and basic understanding of the disease. We developed Helios, an algorithm that integrates genomic data from primary tumors with data from functional RNAi screens to pinpoint driver genes within large recurrently amplified regions of DNA. Applying Helios to breast cancer data identified a set of candidate drivers highly enriched with known drivers (p < 10(-14)). Nine of ten top-scoring Helios genes are known drivers of breast cancer, and in vitro validation of 12 candidates predicted by Helios found ten conferred enhanced anchorage-independent growth, demonstrating Helios's exquisite sensitivity and specificity. We extensively characterized RSF-1, a driver identified by Helios whose amplification correlates with poor prognosis, and found increased tumorigenesis and metastasis in mouse models. We have demonstrated a powerful approach for identifying driver genes and how it can yield important insights into cancer.


Asunto(s)
Algoritmos , Neoplasias de la Mama/genética , Animales , Teorema de Bayes , Neoplasias de la Mama/patología , Línea Celular Tumoral , Variaciones en el Número de Copia de ADN , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Ratones Endogámicos NOD , Ratones SCID , Interferencia de ARN
2.
Cell ; 148(1-2): 244-58, 2012 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-22265415

RESUMEN

p53 is a frequent target for mutation in human tumors, and mutant p53 proteins can actively contribute to tumorigenesis. We employed a three-dimensional culture model in which nonmalignant breast epithelial cells form spheroids reminiscent of acinar structures found in vivo, whereas breast cancer cells display highly disorganized morphology. We found that mutant p53 depletion is sufficient to phenotypically revert breast cancer cells to a more acinar-like morphology. Genome-wide expression analysis identified the mevalonate pathway as significantly upregulated by mutant p53. Statins and sterol biosynthesis intermediates reveal that this pathway is both necessary and sufficient for the phenotypic effects of mutant p53 on breast tissue architecture. Mutant p53 associates with sterol gene promoters at least partly via SREBP transcription factors. Finally, p53 mutation correlates with highly expressed sterol biosynthesis genes in human breast tumors. These findings implicate the mevalonate pathway as a therapeutic target for tumors bearing mutations in p53.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Ácido Mevalónico/metabolismo , Proteína p53 Supresora de Tumor/genética , Línea Celular Tumoral , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Redes y Vías Metabólicas/efectos de los fármacos , Mutación , Prenilación , Regiones Promotoras Genéticas , Simvastatina/farmacología , Proteínas de Unión a los Elementos Reguladores de Esteroles/metabolismo
3.
Genes Dev ; 31(6): 553-566, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28404630

RESUMEN

The female mammary gland is a very dynamic organ that undergoes continuous tissue remodeling during adulthood. Although it is well established that the number of menstrual cycles and pregnancy (in this case transiently) increase the risk of breast cancer, the reasons are unclear. Growing clinical and experimental evidence indicates that improper involution plays a role in the development of this malignancy. Recently, we described the miR-424(322)/503 cluster as an important regulator of mammary epithelial involution after pregnancy. Here, through the analysis of ∼3000 primary tumors, we show that miR-424(322)/503 is commonly lost in a subset of aggressive breast cancers and describe the genetic aberrations that inactivate its expression. Furthermore, through the use of a knockout mouse model, we demonstrate for the first time that loss of miR-424(322)/503 promotes breast tumorigenesis in vivo. Remarkably, we found that loss of miR-424(322)/503 promotes chemoresistance due to the up-regulation of two of its targets: BCL-2 and insulin-like growth factor-1 receptor (IGF1R). Importantly, targeted therapies blocking the aberrant activity of these targets restore sensitivity to chemotherapy. Overall, our studies reveal miR-424(322)/503 as a tumor suppressor in breast cancer and provide a link between mammary epithelial involution, tumorigenesis, and the phenomenon of chemoresistance.


Asunto(s)
Neoplasias de la Mama/genética , MicroARNs/genética , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Resistencia a Antineoplásicos , Femenino , Eliminación de Gen , Genes Supresores de Tumor , Humanos , Neoplasias Mamarias Experimentales/genética , Ratones , Embarazo , Complicaciones Neoplásicas del Embarazo/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Receptor IGF Tipo 1 , Receptores de Somatomedina/genética , Fosfatasas cdc25/genética
4.
EMBO Rep ; 22(12): e53201, 2021 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-34633138

RESUMEN

During the female lifetime, the expansion of the epithelium dictated by the ovarian cycles is supported by a transient increase in the mammary epithelial stem cell population (MaSCs). Notably, activation of Wnt/ß-catenin signaling is an important trigger for MaSC expansion. Here, we report that the miR-424/503 cluster is a modulator of canonical Wnt signaling in the mammary epithelium. We show that mammary tumors of miR-424(322)/503-depleted mice exhibit activated Wnt/ß-catenin signaling. Importantly, we show a strong association between miR-424/503 deletion and breast cancers with high levels of Wnt/ß-catenin signaling. Moreover, miR-424/503 cluster is required for Wnt-mediated MaSC expansion induced by the ovarian cycles. Lastly, we show that miR-424/503 exerts its function by targeting two binding sites at the 3'UTR of the LRP6 co-receptor and reducing its expression. These results unveil an unknown link between the miR-424/503, regulation of Wnt signaling, MaSC fate, and tumorigenesis.


Asunto(s)
Epitelio , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad , Glándulas Mamarias Animales/citología , MicroARNs , Vía de Señalización Wnt , Animales , Neoplasias de la Mama , Carcinogénesis , Línea Celular Tumoral , Células Epiteliales/citología , Epitelio/metabolismo , Femenino , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/metabolismo , Ciclo Menstrual , Ratones , MicroARNs/genética , Células Madre/citología
5.
Genes Dev ; 29(15): 1631-48, 2015 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-26227964

RESUMEN

HER2-positive (HER2(+)) breast adenocarcinomas are a heterogeneous group in which hormone receptor (HR) status influences therapeutic decisions and patient outcome. By combining genome-wide RNAi screens with regulatory network analysis, we identified STAT3 as a critically activated master regulator of HR(-)/HER2(+) tumors, eliciting tumor dependency in these cells. Mechanistically, HR(-)/HER2(+) cells secrete high levels of the interleukin-6 (IL-6) cytokine, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion. Increased calprotectin levels activate signaling pathways involved in proliferation and resistance. Importantly, we demonstrated that inhibition of the IL-6-Janus kinase 2 (JAK2)-STAT3-calprotectin axis with FDA-approved drugs, alone and in combination with HER2 inhibitors, reduced the tumorigenicity of HR(-)/HER2(+) breast cancers, opening novel targeted therapeutic opportunities.


Asunto(s)
Neoplasias de la Mama/fisiopatología , Regulación Neoplásica de la Expresión Génica , Factor de Transcripción STAT3/metabolismo , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Carcinogénesis/genética , Línea Celular Tumoral , Supervivencia Celular/genética , Femenino , Estudio de Asociación del Genoma Completo , Xenoinjertos , Humanos , Interleucina-6/metabolismo , Janus Quinasa 2/metabolismo , Ratones , Ratones SCID , Quinolinas/farmacología , Quinolonas , Interferencia de ARN , Factor de Transcripción STAT3/genética
6.
Genes Dev ; 28(7): 765-82, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24636986

RESUMEN

The mammary gland is a very dynamic organ that undergoes continuous remodeling. The critical regulators of this process are not fully understood. Here we identify the microRNA cluster miR-424(322)/503 as an important regulator of epithelial involution after pregnancy. Through the generation of a knockout mouse model, we found that regression of the secretory acini of the mammary gland was compromised in the absence of miR-424(322)/503. Mechanistically, we show that miR-424(322)/503 orchestrates cell life and death decisions by targeting BCL-2 and IGF1R (insulin growth factor-1 receptor). Furthermore, we demonstrate that the expression of this microRNA cluster is regulated by TGF-ß, a well-characterized regulator of mammary involution. Overall, our data suggest a model in which activation of the TGF-ß pathway after weaning induces the transcription of miR-424(322)/503, which in turn down-regulates the expression of key genes. Here, we unveil a previously unknown, multilayered regulation of epithelial tissue remodeling coordinated by the microRNA cluster miR-424(322)/503.


Asunto(s)
Epitelio/metabolismo , Regulación del Desarrollo de la Expresión Génica , Glándulas Mamarias Animales/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Animales , Muerte Celular/genética , Línea Celular , Femenino , Técnicas de Inactivación de Genes , Humanos , Glándulas Mamarias Animales/citología , Ratones Noqueados , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismo , Destete
7.
Breast Cancer Res ; 17(1): 149, 2015 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-26643555

RESUMEN

INTRODUCTION: Inflammatory breast cancer (IBC) is the most lethal form of breast cancers with a 5-year survival rate of only 40 %. Despite its lethality, IBC remains poorly understood which has greatly limited its therapeutic management. We thus decided to utilize an integrative functional genomic strategy to identify the Achilles' heel of IBC cells. METHODS: We have pioneered the development of genetic tools as well as experimental and analytical strategies to perform RNAi-based loss-of-function studies at a genome-wide level. Importantly, we and others have demonstrated that these functional screens are able to identify essential functions linked to certain cancer phenotypes. Thus, we decided to use this approach to identify IBC specific sensitivities. RESULTS: We identified and validated HDAC6 as a functionally necessary gene to maintain IBC cell viability, while being non-essential for other breast cancer subtypes. Importantly, small molecule inhibitors for HDAC6 already exist and are in clinical trials for other tumor types. We thus demonstrated that Ricolinostat (ACY1215), a leading HDAC6 inhibitor, efficiently controls IBC cell proliferation both in vitro and in vivo. Critically, functional HDAC6 dependency is not associated with genomic alterations at its locus and thus represents a non-oncogene addiction. Despite HDAC6 not being overexpressed, we found that its activity is significantly higher in IBC compared to non-IBC cells, suggesting a possible rationale supporting the observed dependency. CONCLUSION: Our finding that IBC cells are sensitive to HDAC6 inhibition provides a foundation to rapidly develop novel, efficient, and well-tolerated targeted therapy strategies for IBC patients.


Asunto(s)
Histona Desacetilasas/metabolismo , Neoplasias Inflamatorias de la Mama/enzimología , Línea Celular Tumoral , Supervivencia Celular , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Ontología de Genes , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/genética , Humanos , Neoplasias Inflamatorias de la Mama/patología
8.
Cell Death Dis ; 15(4): 296, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38670941

RESUMEN

Genes of the Sprouty family (Spry1-4) restrain signaling by certain receptor tyrosine kinases. Consequently, these genes participate in several developmental processes and function as tumor suppressors in adult life. Despite these important roles, the biology of this family of genes still remains obscure. Here we show that Sprouty proteins are general mediators of cellular senescence. Induction of cellular senescence by several triggers in vitro correlates with upregulation of Sprouty protein levels. More importantly, overexpression of Sprouty genes is sufficient to cause premature cellular senescence, via a conserved N-terminal tyrosine (Tyrosine 53 of Sprouty1). Accordingly, fibroblasts from knockin animals lacking that tyrosine escape replicative senescence. In vivo, heterozygous knockin mice display delayed induction of cellular senescence during cutaneous wound healing and upon chemotherapy-induced cellular senescence. Unlike other functions of this family of genes, induction of cellular senescence appears to be independent of activation of the ERK1/2 pathway. Instead, we show that Sprouty proteins induce cellular senescence upstream of the p38 pathway in these in vitro and in vivo paradigms.


Asunto(s)
Senescencia Celular , Fibroblastos , Proteínas de la Membrana , Animales , Ratones , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Humanos , Fibroblastos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Sistema de Señalización de MAP Quinasas , Cicatrización de Heridas
9.
J Biol Chem ; 286(27): 24350-63, 2011 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-21572038

RESUMEN

The neuregulins (NRGs) play important roles in animal development and homeostasis, and their deregulation has been linked to diseases such as cancer and schizophrenia. The NRGs belong to the epidermal growth factor (EGF) family of transmembrane growth factors. Although NRGs may be synthesized as transmembrane proteins (the pro-NRGs), some of them lack an N-terminal signal sequence, raising the question of how these pro-NRGs are directed to the plasma membrane. Here we have explored the domains of pro-NRGs that are required for their membrane anchoring, cell surface exposure, and biological activity. We show that an internal hydrophobic region acts as a membrane-anchoring domain, but other regions of pro-NRG are required for proper sorting to the plasma membrane. Using mutants that are located in different subcellular compartments, we show that only plasma membrane-exposed pro-NRG is biologically active. At this location, the pro-NRGs may act as transautocrine molecules (i.e. as membrane factors able to activate receptors present in cells that are in physical contact with the pro-NRG-producing cells (in trans) or capable of activating receptors present in the pro-NRG-producing cells (in cis)).


Asunto(s)
Comunicación Autocrina/fisiología , Membrana Celular/metabolismo , Proteínas de la Membrana/metabolismo , Neurregulinas/metabolismo , Transducción de Señal/fisiología , Línea Celular Tumoral , Membrana Celular/genética , Humanos , Proteínas de la Membrana/genética , Neurregulinas/genética , Señales de Clasificación de Proteína/fisiología , Estructura Terciaria de Proteína
11.
JCI Insight ; 7(14)2022 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-35737463

RESUMEN

The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream of the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. Consistent with this, mice lacking the S6k1 gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumors. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, decreased mTORC1 signaling in fat (but increased in the liver) segregated with defective epithelial-mesenchymal transition and the impaired expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks.


Asunto(s)
Hígado Graso , Serina-Treonina Quinasas TOR , Animales , Dieta , Hígado Graso/tratamiento farmacológico , Hígado Graso/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo
12.
Adv Sci (Weinh) ; : e2204211, 2022 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-36373729

RESUMEN

Clinical management of endometrial cancer (EC) is handicapped by the limited availability of second line treatments and bona fide molecular biomarkers to predict recurrence. These limitations have hampered the treatment of these patients, whose survival rates have not improved over the last four decades. The advent of coordinated studies such as The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA_UCEC) has partially solved this issue, but the lack of proper experimental systems still represents a bottleneck that precludes translational studies from successful clinical testing in EC patients. Within this context, the first study reporting the generation of a collection of endometrioid-EC-patient-derived orthoxenograft (PDOX) mouse models is presented that is believed to overcome these experimental constraints and pave the way toward state-of-the-art precision medicine in EC. The collection of primary tumors and derived PDOXs is characterized through an integrative approach based on transcriptomics, mutational profiles, and morphological analysis; and it is demonstrated that EC tumors engrafted in the mouse uterus retain the main molecular and morphological features from analogous tumor donors. Finally, the molecular properties of these tumors are harnessed to assess the therapeutic potential of trastuzumab, a human epidermal growth factor receptor 2 (HER2) inhibitor with growing interest in EC, using patient-derived organotypic multicellular tumor spheroids and in vivo experiments.

13.
J Exp Clin Cancer Res ; 41(1): 285, 2022 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-36163066

RESUMEN

BACKGROUND: Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel effective targeted treatments for HER2/GSDMB aggressive tumors. METHODS: Different in vitro approaches (immunoblot, qRT-PCR, flow cytometry, proteomic analysis, immunoprecipitation, and confocal/electron microscopy) were performed in HER2 breast and gastroesophageal carcinoma cell models. Results were then validated using in vivo preclinical animal models and analyzing human breast and gastric cancer samples. RESULTS: GSDMB up-regulation renders HER2 cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Accordingly, the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response of GSDMB-positive cancers in vitro and in zebrafish and mice tumor xenograft in vivo models. Mechanistically, GSDMB N-terminal domain interacts with the key components of the autophagy machinery LC3B and Rab7, facilitating the Rab7 activation during pro-survival autophagy in response to anti-HER2 therapies. Finally, we validated these results in clinical samples where GSDMB/Rab7/LC3B co-expression associates significantly with relapse in HER2 breast and gastric cancers. CONCLUSION: Our findings uncover for the first time a functional link between GSDMB over-expression and protective autophagy in response to HER2-targeted therapies. GSDMB behaves like an autophagy adaptor and plays a pivotal role in modulating autophagosome maturation through Rab7 activation. Finally, our results provide a new and accessible therapeutic approach for HER2/GSDMB + cancers with adverse clinical outcome.


Asunto(s)
Neoplasias de la Mama , Receptor ErbB-2 , Animales , Autofagia , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Línea Celular Tumoral , Cloroquina/farmacología , Resistencia a Antineoplásicos , Femenino , Humanos , Lapatinib/farmacología , Ratones , Recurrencia Local de Neoplasia , Proteómica , Receptor ErbB-2/genética , Pez Cebra
14.
Adv Sci (Weinh) ; 9(4): e2104759, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34898027

RESUMEN

The H19X-encoded miR-424(322)/503 cluster regulates multiple cellular functions. Here, it is reported for the first time that it is also a critical linchpin of fat mass expansion. Deletion of this miRNA cluster in mice results in obesity, while increasing the pool of early adipocyte progenitors and hypertrophied adipocytes. Complementary loss and gain of function experiments and RNA sequencing demonstrate that miR-424(322)/503 regulates a conserved genetic program involved in the differentiation and commitment of white adipocytes. Mechanistically, it is demonstrated that miR-424(322)/503 targets γ-Synuclein (SNCG), a factor that mediates this program rearrangement by controlling metabolic functions in fat cells, allowing adipocyte differentiation and adipose tissue enlargement. Accordingly, diminished miR-424(322) in mice and obese humans co-segregate with increased SNCG in fat and peripheral blood as mutually exclusive features of obesity, being normalized upon weight loss. The data unveil a previously unknown regulatory mechanism of fat mass expansion tightly controlled by the miR-424(322)/503 through SNCG.


Asunto(s)
Tejido Adiposo/metabolismo , Diferenciación Celular , MicroARNs/metabolismo , Proteínas de Neoplasias/metabolismo , gamma-Sinucleína/metabolismo , Adipogénesis , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Proteínas de Neoplasias/genética , gamma-Sinucleína/genética
15.
Cancers (Basel) ; 13(24)2021 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-34944822

RESUMEN

About 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients' quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone tropism is crucial. For this purpose, we generated an animal model with high penetrance to metastasize to bone using an intracardiac percutaneous injection of PC3 cells to identify PCa metastasis-promoting factors. Using genomic high-throughput analysis we identified a miRNA signature involved in bone metastasis that also presents potential as a biomarker of PCa progression in human samples. In particular, the downregulation of miR-135b favored the incidence of bone metastases by significantly increasing PCa cells' migratory capacity. Moreover, the PLAG1, JAKMIP2, PDGFA, and VTI1b target genes were identified as potential mediators of miR-135b's role in the dissemination to bone. In this study, we provide a genomic signature involved in PCa bone growth, contributing to a better understanding of the mechanisms responsible for this process. In the future, our results could ultimately translate into promising new therapeutic targets for the treatment of lethal PCa.

16.
Mol Biol Cell ; 18(2): 380-93, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17108327

RESUMEN

The neuregulins (NRGs) play important roles in animal physiology, and their disregulation has been linked to diseases such as cancer or schizophrenia. The NRGs may be produced as transmembrane proteins (proNRGs), even though they lack an N-terminal signal sequence. This raises the question of how NRGs are sorted to the plasma membrane. It is also unclear whether in their transmembrane state, the NRGs are biologically active. During studies aimed at solving these questions, we found that deletion of the extracellular juxtamembrane region termed the linker, decreased cell surface exposure of the mutant proNRG(DeltaLinker), and caused its entrapment at the cis-Golgi. We also found that cell surface-exposed transmembrane NRG forms retain biological activity. Thus, a mutant whose cleavage is impaired but is correctly sorted to the plasma membrane activated ErbB receptors in trans and also stimulated proliferation. Because the linker is implicated in surface sorting and the regulation of the cleavage of transmembrane NRGs, our data indicate that this region exerts multiple important roles in the physiology of NRGs.


Asunto(s)
Membrana Celular/metabolismo , Neurregulina-1/genética , Neurregulina-1/metabolismo , Señales de Clasificación de Proteína , Secuencia de Aminoácidos , Animales , Membrana Celular/química , Células Cultivadas , Receptores ErbB/metabolismo , Humanos , Ratones , Datos de Secuencia Molecular , Mutación , Neurregulina-1/análisis , Señales de Clasificación de Proteína/genética , Transporte de Proteínas , Ratas , Eliminación de Secuencia
17.
Clin Cancer Res ; 14(11): 3237-41, 2008 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-18519747

RESUMEN

The neuregulins represent the largest subclass of polypeptide factors of the epidermal growth factor family of ligands. These molecules are synthesized as membrane-bound, biologically active growth factors that act by binding to the HER/ErbB receptor tyrosine kinases. Preclinical data have indicated that increased expression and function of neuregulins may provoke cancer. Furthermore, neuregulin expression has been detected in several neoplasias, and their presence may correlate with response to treatments that target the HER receptors such as trastuzumab. In addition, the neuregulins have also been implicated in resistance to anti-HER therapies. Therefore, targeting of the neuregulins may be helpful in neoplastic diseases in which these polypeptide factors contribute to tumor generation and/or maintenance.


Asunto(s)
Neoplasias/metabolismo , Neurregulinas/metabolismo , Animales , Transformación Celular Neoplásica/metabolismo , Humanos
18.
Mol Oncol ; 12(7): 1061-1076, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29683256

RESUMEN

The neuregulins (NRGs) represent a large family of membrane-anchored growth factors, whose deregulation may contribute to the pathogenesis of several tumors. In fact, targeting of NRG-activated pathways has demonstrated clinical benefit. To improve the efficacy of anti-NRG therapies, it is essential to gain insights into the regions of NRGs that favor their pro-oncogenic properties. Here, we have addressed the protumorigenic impact of different NRG domains. To do this, deletion mutants affecting different NRG domains were expressed in 293 and MCF7 cells. Of the five forms studied, only the wild-type and a mutant lacking the Ig-like domain (NRGΔIg ) were properly sorted to the plasma membrane. Both forms were released as soluble forms to the culture media. However, the mutant NRGΔIg failed to efficiently activate HER2 and HER3 receptors, signaling pathways, and cell proliferation when compared to wild-type NRG. Treatment with trastuzumab, a humanized antibody used in the breast cancer clinic, inhibited the constitutive activation of HER2, HER3, and downstream signaling in MCF7 cells constitutively expressing wild-type NRG. In contrast, this treatment had a marginal effect on MCF7-NRGΔIg cells. This study demonstrates that the Ig-like region of NRGs exerts an important role in their capability to activate ErbB/HER receptors and mitogenic responses. Strategies aimed at targeting NRGs should consider that fact to improve neutralization of the pro-oncogenic properties of NRGs.


Asunto(s)
Dominios de Inmunoglobulinas , Neurregulinas/química , Neurregulinas/metabolismo , Receptor ErbB-2/metabolismo , Membrana Celular/metabolismo , Proliferación Celular , Humanos , Células MCF-7 , Proteínas Mutantes/metabolismo , Transducción de Señal , Solubilidad , Relación Estructura-Actividad , Trastuzumab
19.
Cancer Discov ; 8(5): 582-599, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29510988

RESUMEN

High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator proteins that were conserved across independent cohorts. A 10-protein transcriptional module-centered around a TEAD4-MYCN positive feedback loop-emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional coactivators YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN-deregulated neuroblastomas.Significance: Despite progress in understanding of neuroblastoma genetics, little progress has been made toward personalized treatment. Here, we present a framework to determine the downstream effectors of the genetic alterations sustaining neuroblastoma subtypes, which can be easily extended to other tumor types. We show the critical effect of disrupting a 10-protein module centered around a YAP/TAZ-independent TEAD4-MYCN positive feedback loop in MYCNAmp neuroblastomas, nominating TEAD4 as a novel candidate for therapeutic intervention. Cancer Discov; 8(5); 582-99. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 517.


Asunto(s)
Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Musculares/genética , Proteína Proto-Oncogénica N-Myc/genética , Neuroblastoma/genética , Neuroblastoma/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos , Factores de Transcripción/genética , Aciltransferasas , Proteínas de Ciclo Celular , Línea Celular Tumoral , Biología Computacional/métodos , Proteínas de Unión al ADN/metabolismo , Perfilación de la Expresión Génica , Humanos , Proteínas Musculares/metabolismo , Proteína Proto-Oncogénica N-Myc/metabolismo , Estadificación de Neoplasias , Neuroblastoma/diagnóstico , Proteínas Nucleares/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Interferencia de ARN , Factores de Transcripción de Dominio TEA , Factores de Transcripción/metabolismo , Activación Transcripcional
20.
Autophagy ; 13(3): 608-624, 2017 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-28055301

RESUMEN

Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC.


Asunto(s)
Autofagia , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Terapia Molecular Dirigida , Animales , Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Progresión de la Enfermedad , Neoplasias Endometriales/enzimología , Neoplasias Endometriales/ultraestructura , Estrés del Retículo Endoplásmico/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Ratones Desnudos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacología , Niacinamida/uso terapéutico , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Sorafenib , Ensayos Antitumor por Modelo de Xenoinjerto
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