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1.
Mol Cancer Res ; 20(6): 883-894, 2022 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-35247910

RESUMEN

Recent work has established that SWI-independent-3 (SIN3) chromatin modification complexes play key roles in cancer progression. We previously demonstrated that knockdown of SIN3A expression promotes human breast cancer cell invasion and metastasis; however, the levels of SIN3A in patient breast carcinoma are not known. We therefore examined SIN3A mRNA and protein in patient tissues and determined that SIN3A expression is lower in breast carcinoma relative to normal breast. Given the 3'-untranslated region (UTR) of SIN3A has several conserved binding sites for oncogenic miRNA, we hypothesized that SIN3A is targeted by miRNA and found that ectopic miR-183 results in decreased SIN3A in breast carcinoma cell lines. Functionally, we demonstrate that miR-183 promotes breast cancer cell migration and invasion in a SIN3A-dependent manner and ectopic miR-183 promotes metastasis in vivo. Patients with breast cancer with high levels of miR-183 and low levels of SIN3A have the shortest overall survival. Given the critical link between metastasis and survival in patients with breast cancer, it is of utmost importance to identify clinically relevant genes involved in metastasis. Here, we report for the first time the aberrant expression of the putative metastasis suppressing gene SIN3A in human breast cancers and propose a mechanism of SIN3A suppression by miR-183. IMPLICATIONS: SIN3A expression is decreased in metastatic breast cancer in part due to miR-183.


Asunto(s)
Neoplasias de la Mama , MicroARNs , Regiones no Traducidas 3' , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Invasividad Neoplásica/genética , Metástasis de la Neoplasia
2.
PLoS One ; 16(11): e0259128, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34788285

RESUMEN

Breast Cancer Metastasis Suppressor 1 (BRMS1) expression is associated with longer patient survival in multiple cancer types. Understanding BRMS1 functionality will provide insights into both mechanism of action and will enhance potential therapeutic development. In this study, we confirmed that the C-terminus of BRMS1 is critical for metastasis suppression and hypothesized that critical protein interactions in this region would explain its function. Phosphorylation status at S237 regulates BRMS1 protein interactions related to a variety of biological processes, phenotypes [cell cycle (e.g., CDKN2A), DNA repair (e.g., BRCA1)], and metastasis [(e.g., TCF2 and POLE2)]. Presence of S237 also directly decreased MDA-MB-231 breast carcinoma migration in vitro and metastases in vivo. The results add significantly to our understanding of how BRMS1 interactions with Sin3/HDAC complexes regulate metastasis and expand insights into BRMS1's molecular role, as they demonstrate BRMS1 C-terminus involvement in distinct protein-protein interactions.


Asunto(s)
Neoplasias de la Mama , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de Neoplasias , Proteínas Represoras , Complejo Correpresor Histona Desacetilasa y Sin3
3.
Cancer Res ; 81(8): 1942-1953, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33558335

RESUMEN

miRNA rarely possess pan-oncogenic or tumor-suppressive properties. Most miRNAs function under tissue-specific contexts, acting as either tumor suppressors in one tissue, promoting oncogenesis in another, or having no apparent role in the regulation of processes associated with the hallmarks of cancer. What has been less clear is the role of miRNAs within cell types of the same tissue and the ability within each cell type to contribute to oncogenesis. In this study, we characterize the role of one such tissue-specific miRNA, miR-31, recently identified as the most oncogenic miRNA in lung adenocarcinoma, across the histologic spectrum of human lung cancer. Compared with normal lung tissue, miR-31 was overexpressed in patient lung adenocarcinoma, squamous cell carcinoma, and large-cell neuroendocrine carcinoma, but not small-cell carcinoma or carcinoids. miR-31 promoted tumor growth in mice of xenografted human adenocarcinoma and squamous cell carcinoma cell lines, but not in large- or small-cell carcinoma lines. While miR-31 did not promote primary tumor growth of large- and small-cell carcinoma, it did promote spontaneous metastasis. Mechanistically, miR-31 altered distinct cellular signaling programs within each histologic subtype, resulting in distinct phenotypic differences. This is the first report distinguishing diverse functional roles for this miRNA across the spectrum of lung cancers and suggests that miR-31 has broad clinical value in human lung malignancy. SIGNIFICANCE: These findings demonstrate the oncogenic properties of miR-31 in specific subtypes of lung cancer and highlight it as a potential therapeutic target in these subtypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/1942/F1.large.jpg.


Asunto(s)
Adenocarcinoma del Pulmón/metabolismo , Carcinoma Neuroendocrino/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/metabolismo , MicroARNs/metabolismo , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Animales , Carcinoma Adenoescamoso/genética , Carcinoma Adenoescamoso/metabolismo , Carcinoma Adenoescamoso/patología , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/secundario , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Proliferación Celular , Bases de Datos Genéticas , Femenino , Humanos , Neoplasias Hepáticas/secundario , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Masculino , Ratones , Ratones Desnudos , Metástasis de la Neoplasia/genética , Trasplante de Neoplasias , Especificidad de Órganos , Transducción de Señal/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/secundario , Proteínas Supresoras de Tumor/metabolismo
4.
Adv Sci (Weinh) ; 7(22): 2002747, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33240783

RESUMEN

Recent studies have proven that long noncoding RNAs (lncRNAs) exhibit regulatory functions of both DNA damage response (DDR) and endoplasmic reticulum (ER) stress. Herein, ER stress-induced lncRNA transcriptomic changes are reported in human oral squamous cell carcinoma (OSCC) cells and a novel lncRNA HITTERS ( H ERPUD1 intronic transcript of ER stress) is identified as the most significantly upregulated lncRNA. It is shown that HITTERS is a nucleus-located lncRNA including two transcript variants. HITTERS lacks an independent promoter but shares the same promoter with HERPUD1. HITTERS is transcriptionally regulated by Activating Transcription Factor (ATF) 6, ATF4, X-Box Binding Protein 1 (XBP1), and DNA methylation. In human OSCC tissues, HITTERS is significantly correlated with OSCC clinicopathological features and prognosis. Gain- and loss-of-function studies reveal that HITTERS promotes OSCC proliferation and invasion via influencing the expression of growth factor receptors and the downstream pathways. Once ER stress is triggered, HITTERS significantly attenuates ER stress-induced apoptosis both in vivo and in vitro. Mechanically, HITTERS functions as RNA scaffold to promote MRE11-RAD50-NBS1 complex formation in the repair of ER stress-induced DNA damage. To sum up, this study presents a novel lncRNA, namely HITTERS, which links ER stress and DDR together in OSCC.

5.
Mil Med Res ; 7(1): 48, 2020 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-33038921

RESUMEN

BACKGROUND: p53 and DIRAS3 are tumor suppressors that are frequently silenced in tumors. In this study, we sought to determine whether the concurrent re-expression of p53 and DIRAS3 could effectively induce head and neck squamous cell carcinoma (HNSCC) cell death. METHODS: CAL-27 and SCC-25 cells were treated with Ad-DIRAS3 and rAd-p53 to induce re-expression of DIRAS3 and p53 respectively. The effects of DIRAS3 and p53 re-expression on the growth and apoptosis of HNSCC cells were examined by TUNEL assay, flow cytometric analysis and MTT. The effects of DIRAS3 and p53 re-expression on Akt phosphorylation, oncogene expression, and the interaction of 4E-BP1 with eIF4E were determined by real-time PCR, Western blotting and immunoprecipitation analysis. The ability of DIRAS3 and p53 re-expression to induce autophagy was evaluated by transmission electron microscopy, LC3 fluorescence microscopy and Western blotting. The effects of DIRAS3 and p53 re-expression on HNSCC growth were evaluated by using an orthotopic xenograft mouse model. RESULTS: TUNEL assay and flow cytometric analysis showed that the concurrent re-expression of DIRAS3 and p53 significantly induced apoptosis (P < 0.001). MTT and flow cytometric analysis revealed that DIRAS3 and p53 re-expression significantly inhibited proliferation and induced cell cycle arrest (P < 0.001). Mechanistically, the concurrent re-expression of DIRAS3 and p53 down-regulated signal transducer and activation of transcription 3 (STAT3) and up-regulated p21WAF1/CIP1 and Bax (P < 0.001). DIRAS3 and p53 re-expression also inhibited Akt phosphorylation, increased the interaction of eIF4E with 4E-BP1, and reduced the expression of c-Myc, cyclin D1, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), epidermal growth factor receptor (EGFR) and Bcl-2 (P < 0.001). Moreover, the concurrent re-expression of DIRAS3 and p53 increased the percentage of cells with GFP-LC3 puncta compared with that in cells treated with control adenovirus (50.00% ± 4.55% vs. 4.67% ± 1.25%, P < 0.001). LC3 fluorescence microscopy and Western blotting further showed that DIRAS3 and p53 re-expression significantly promoted autophagic activity but also inhibited autophagic flux, resulting in overall impaired autophagy. Finally, the concurrent re-expression of DIRAS3 and p53 significantly decreased the tumor volume compared with the control group in a HNSCC xenograft mouse model [(3.12 ± 0.75) mm3 vs. (189.02 ± 17.54) mm3, P < 0.001]. CONCLUSIONS: The concurrent re-expression of DIRAS3 and p53 is a more effective approach to HNSCC treatment than current treatment strategies.


Asunto(s)
Autofagia/genética , Fragmentos de Péptidos/farmacología , Carcinoma de Células Escamosas de Cabeza y Cuello/complicaciones , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Proteína p53 Supresora de Tumor/farmacología , Proteínas de Unión al GTP rho/farmacología , Animales , Apoptosis/genética , Células Cultivadas , Expresión Génica/genética , Ratones , Ratones Endogámicos BALB C , Fragmentos de Péptidos/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/fisiopatología , Proteína p53 Supresora de Tumor/uso terapéutico , Proteínas de Unión al GTP rho/uso terapéutico
6.
Cancer Res ; 79(12): 3011-3027, 2019 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-31053634

RESUMEN

Metastasis is the primary cause of cancer morbidity and mortality. The process involves a complex interplay between intrinsic tumor cell properties as well as interactions between cancer cells and multiple microenvironments. The outcome is the development of a nearby or distant discontiguous secondary mass. To successfully disseminate, metastatic cells acquire properties in addition to those necessary to become neoplastic. Heterogeneity in mechanisms involved, routes of dissemination, redundancy of molecular pathways that can be utilized, and the ability to piggyback on the actions of surrounding stromal cells makes defining the hallmarks of metastasis extraordinarily challenging. Nonetheless, this review identifies four distinguishing features that are required: motility and invasion, ability to modulate the secondary site or local microenvironments, plasticity, and ability to colonize secondary tissues. By defining these first principles of metastasis, we provide the means for focusing efforts on the aspects of metastasis that will improve patient outcomes.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/metabolismo , Neoplasias/patología , Microambiente Tumoral , Animales , Humanos , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/metabolismo
7.
Oncotarget ; 7(48): 78713-78725, 2016 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-27780928

RESUMEN

SIN3 corepressor complexes play important roles in both normal development and breast cancer. Mammalian cells have two paralogs of SIN3 (SIN3A and SIN3B) that are encoded by distinct genes and have unique functions in many developmental processes. However, specific roles for SIN3A and SIN3B in breast cancer progression have not been characterized. We generated stable knockdown cells of SIN3 paralogs individually and in combination using three non-overlapping shRNA. Stable knockdown of SIN3B caused a significant decrease in transwell invasion through Matrigel and decreased the number of invasive colonies when grown in a 3D extracellular matrix. Conversely, stable knockdown of SIN3A significantly increased transwell invasion and increased the number of invasive colonies. These results were corroborated in vivo in which SIN3B knockdown significantly decreased and SIN3A knockdown increased experimental lung metastases. RNA sequencing was used to identify unique targets and biological pathways that were altered upon knockdown of SIN3A compared to SIN3B. Additionally, we analyzed microarray data sets to identify correlations of SIN3A and SIN3B expression with survival in patients with breast cancer. These data sets indicated that high mRNA expression of SIN3A as well as low mRNA expression of SIN3B correlates with longer relapse free survival specifically in patients with triple negative breast cancer which corresponds with our in vitro and in vivo data. These results demonstrate key functional differences between SIN3 paralogs in regulating the process of breast cancer metastasis and suggest metastasis suppressive roles of SIN3A and metastasis promoting roles of SIN3B.


Asunto(s)
Movimiento Celular , Neoplasias Pulmonares/metabolismo , Proteínas Represoras/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Ratones Desnudos , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Análisis de Secuencia por Matrices de Oligonucleótidos , Interferencia de ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Represoras/genética , Transducción de Señal , Complejo Correpresor Histona Desacetilasa y Sin3 , Factores de Tiempo , Transfección , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/terapia
8.
Oncol Lett ; 12(1): 523-529, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27347175

RESUMEN

Breast cancer cells are heterogeneous in their ability to invade and fully metastasize, and thus also in their capacity to survive the numerous stresses encountered throughout the multiple steps of the metastatic cascade. Considering the role of autophagy as a survival response to stress, the present study hypothesized that distinct populations of breast cancer cells may possess an altered autophagic capacity that influences their metastatic potential. It was observed that a metastatic breast cancer cell line, MDA-MB-231, that was sensitive to autophagic induction additionally possessed the ability to proliferate following nutrient deprivation. Furthermore, a selected subpopulation of these cells that survived multiple exposures to starvation conditions demonstrated a heightened response to autophagic induction compared to their parent cells. Although this subpopulation maintained a more grape-like pattern in three-dimensional culture compared to the extended spikes of the parent population, autophagic induction in this subpopulation elicited an invasive phenotype with extended spikes. Taken together, these results suggest that autophagic induction may contribute to the ability of distinct breast cancer cell populations to survive and invade.

9.
Oncol Lett ; 11(1): 633-641, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26870258

RESUMEN

Every year, a large number of women succumb to metastatic breast cancer due to a lack of curative approaches for this disease. Adiponectin (AdipoQ) is the most abundant of the adipocyte-secreted adipokines. In recent years, there has been an interest in the use of AdipoQ and AdipoQ receptor agonists as therapeutic agents for the treatment of breast cancer. However, while multiple epidemiological studies have previously indicated that low levels of circulating plasma AdipoQ portend poor prognosis in patients with breast cancer, recent studies have reported that elevated expression levels of AdipoQ in breast tissue are correlated with advanced stages of the disease. Thus, the aim of the present study was to clarify the mechanism by which AdipoQ in breast tissue acts directly on tumor cells to regulate the early steps of breast cancer metastasis. In the present study, the effects of different AdipoQ isoforms on the metastatic potential of human breast cancer cells were investigated. The results revealed that globular adiponectin (gAd) promoted invasive cell morphology and significantly increased the migration and invasion abilities of breast cancer cells, whereas full-length adiponectin (fAd) had no effect on these cells. Additionally, gAd, but not fAd, increased the expression levels of microtubule-associated protein 1 light chain 3 beta (LC3B)-II and intracellular LC3B puncta, which are indicators of autophagosome formation, thus suggesting autophagic induction by gAd. Furthermore, the inhibition of autophagic function by autophagy-related protein 7 knockdown attenuated the gAd-induced increase in invasiveness in breast cancer cells. Therefore, the results of the present study suggested that a specific AdipoQ isoform may enhance breast cancer invasion, possibly via autophagic induction. Understanding the roles of the different AdipoQ isoforms as microenvironmental regulatory molecules may aid the development of effective AdipoQ-based treatments for breast cancer.

10.
Cancer Immunol Res ; 3(7): 727-40, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25649351

RESUMEN

Suppressor of cytokine signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway and generally function as tumor suppressors. The absence of SOCS3 in particular leads to heightened activation of the STAT3 transcription factor, which has a striking ability to promote tumor survival while suppressing antitumor immunity. We report for the first time that genetic deletion of SOCS3, specifically in myeloid cells, significantly enhances tumor growth, which correlates with elevated levels of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, and diminishes CD8(+) T-cell infiltration in tumors. The importance of MDSCs in promoting tumor growth is documented by reduced tumor growth upon depletion of MDSCs. Furthermore, SOCS3-deficient bone-marrow-derived cells exhibit heightened STAT3 activation and preferentially differentiate into the Gr-1(+)CD11b(+)Ly6G(+) MDSC phenotype. Importantly, we identify G-CSF as a critical factor secreted by the tumor microenvironment that promotes development of MDSCs via a STAT3-dependent pathway. Abrogation of tumor-derived G-CSF reduces the proliferation and accumulation of Gr-1(+)CD11b(+) MDSCs and inhibits tumor growth. These findings highlight the critical function of SOCS3 as a negative regulator of MDSC development and function via inhibition of STAT3 activation.


Asunto(s)
Células Mieloides/inmunología , Factor de Transcripción STAT3/genética , Transducción de Señal/genética , Proteínas Supresoras de la Señalización de Citocinas/genética , Linfocitos T/inmunología , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína 3 Supresora de la Señalización de Citocinas , Microambiente Tumoral
11.
Oncolytic Virother ; 4: 63-73, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-27512671

RESUMEN

New therapies for metastatic breast cancer patients are urgently needed. The long-term survival rates remain unacceptably low for patients with recurrent disease or disseminated metastases. In addition, existing therapies often cause a variety of debilitating side effects that severely impact quality of life. Oncolytic viruses constitute a developing therapeutic modality in which interest continues to build due to their ability to spare normal tissue while selectively destroying tumor cells. A number of different viruses have been used to develop oncolytic agents for breast cancer, including herpes simplex virus, adenovirus, vaccinia virus, measles virus, reovirus, and others. In general, clinical trials for several cancers have demonstrated excellent safety records and evidence of efficacy. However, the impressive tumor responses often observed in preclinical studies have yet to be realized in the clinic. In order for the promise of oncolytic virotherapy to be fully realized for breast cancer patients, effectiveness must be demonstrated in metastatic disease. This review provides a summary of oncolytic virotherapy strategies being developed to target metastatic breast cancer.

12.
J Mol Med (Berl) ; 92(10): 1015-23, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24903246

RESUMEN

Adipokines within the tumor microenvironment may play important roles in regulating the early steps of breast cancer metastasis. Adiponectin (AdipoQ) is the most abundant adipokine and exists in multiple forms: full-length multimers (fAd) and a cleaved, globular isoform (gAd). While these isoforms are observed as having distinct biological properties, nearly all investigation into AdipoQ in breast cancer has focused on the antitumor roles of fAd, while mostly ignoring gAd. However, evidence from other disease settings suggests that gAd is linked to processes known to promote metastasis. Here, we discuss key areas in which knowledge about AdipoQ in breast cancer is lacking, expressly focusing on data suggesting that gAd is elevated in the microenvironment and may act directly on invasive breast cancer cells to support their initial metastatic progression. We discuss autophagy as a potential mechanism of action for this effect. Overall, given that AdipoQ and AdipoQ receptor agonists have been proposed as therapeutic strategies, it is necessary to better understand the various functions of these regulatory molecules in metastatic breast cancer. Doing so will help ensure the most effective approaches to treating this disease, for which there remain no curative options.


Asunto(s)
Adiponectina/metabolismo , Autofagia , Neoplasias de la Mama/metabolismo , Animales , Neoplasias de la Mama/patología , Femenino , Humanos
13.
PLoS One ; 9(3): e92919, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24651853

RESUMEN

New therapies are needed for metastatic breast cancer patients. Oncolytic herpes simplex virus (oHSV) is an exciting therapy being developed for use against aggressive tumors and established metastases. Although oHSV have been demonstrated safe in clinical trials, a lack of sufficient potency has slowed the clinical application of this approach. We utilized histone deacetylase (HDAC) inhibitors, which have been noted to impair the innate antiviral response and improve gene transcription from viral vectors, to enhance the replication of oHSV in breast cancer cells. A panel of chemically diverse HDAC inhibitors were tested at three different doses (<,  = , and >LD50) for their ability to modulate the replication of oHSV in breast cancer cells. Several of the tested HDAC inhibitors enhanced oHSV replication at low multiplicity of infection (MOI) following pre-treatment of the metastatic breast cancer cell line MDA-MB-231 and the oHSV-resistant cell line 4T1, but not in the normal breast epithelial cell line MCF10A. Inhibitors of class I HDACs, including pan-selective compounds, were more effective for increasing oHSV replication compared to inhibitors that selectively target class II HDACs. These studies demonstrate that select HDAC inhibitors increase oHSV replication in breast cancer cells and provides support for pre-clinical evaluation of this combination strategy.


Asunto(s)
Vectores Genéticos/genética , Inhibidores de Histona Desacetilasas/farmacología , Virus Oncolíticos/genética , Simplexvirus/genética , Replicación Viral/efectos de los fármacos , Animales , Neoplasias de la Mama , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Ratones
14.
Mol Carcinog ; 53(12): 1011-26, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24000122

RESUMEN

Metastatic dissemination is a multi-step process that depends on cancer cells' ability to respond to microenvironmental cues by adapting adhesion abilities and undergoing cytoskeletal rearrangement. Breast Cancer Metastasis Suppressor 1 (BRMS1) affects several steps of the metastatic cascade: it decreases survival in circulation, increases susceptibility to anoikis, and reduces capacity to colonize secondary organs. In this report, BRMS1 expression is shown to not significantly alter expression levels of integrin monomers, while time-lapse and confocal microscopy revealed that BRMS1-expressing cells exhibited reduced activation of both ß1 integrin and focal adhesion kinase, and decreased localization of these molecules to sites of focal adhesions. Short-term plating of BRMS1-expressing cells onto collagen or fibronectin markedly decreased cytoskeletal reorganization and formation of cellular adhesion projections. Under 3D culture conditions, BRMS1-expressing cells remained rounded and failed to reorganize their cytoskeleton and form invasive colonies. Taken together, BRMS1-expressing breast cancer cells are greatly attenuated in their ability to respond to microenvironment changes. © 2013 Wiley Periodicals, Inc.


Asunto(s)
Neoplasias de la Mama/genética , Adhesión Celular/genética , Metástasis de la Neoplasia/genética , Proteínas de Neoplasias/genética , Línea Celular Tumoral , Citoesqueleto/genética , Femenino , Proteína-Tirosina Quinasas de Adhesión Focal/genética , Humanos , Integrina beta1/genética , Proteínas Represoras
15.
PLoS One ; 8(6): e68348, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23840849

RESUMEN

Solid tumors are characterized by regions of low oxygen tension (OT), which play a central role in tumor progression and resistance to therapy. Low OT affects mitochondrial function and for the cells to survive, mitochondria must functionally adapt to low OT to maintain the cellular bioenergetics. In this study, a novel experimental approach was developed to examine the real-time bioenergetic changes in breast cancer cells (BCCs) during adaptation to OT (from 20% to <1% oxygen) using sensitive extracellular flux technology. Oxygen was gradually removed from the medium, and the bioenergetics of metastatic BCCs (MDA-MB-231 and MCF10CA clones) was compared with non-tumorigenic (MCF10A) cells. BCCs, but not MCF10A, rapidly responded to low OT by stabilizing HIF-1α and increasing HIF-1α responsive gene expression and glucose uptake. BCCs also increased extracellular acidification rate (ECAR), which was markedly lower in MCF10A. Interestingly, BCCs exhibited a biphasic response in basal respiration as the OT was reduced from 20% to <1%. The initial stimulation of oxygen consumption is found to be due to increased mitochondrial respiration. This effect was HIF-1α-dependent, as silencing HIF-1α abolished the biphasic response. During hypoxia and reoxygenation, BCCs also maintained oxygen consumption rates at specific OT; however, HIF-1α silenced BCC were less responsive to changes in OT. Our results suggest that HIF-1α provides a high degree of bioenergetic flexibility under different OT which may confer an adaptive advantage for BCC survival in the tumor microenvironment and during invasion and metastasis. This study thus provides direct evidence for the cross-talk between HIF-1α and mitochondria during adaptation to low OT by BCCs and may be useful in identifying novel therapeutic agents that target the bioenergetics of BCCs in response to low OT.


Asunto(s)
Neoplasias de la Mama/fisiopatología , Metabolismo Energético/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Mitocondrias/patología , Mitocondrias/fisiología , Metástasis de la Neoplasia/fisiopatología , Oxígeno/metabolismo , Adaptación Biológica/genética , Adaptación Biológica/fisiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Respiración de la Célula/genética , Respiración de la Célula/fisiología , Metabolismo Energético/genética , Femenino , Glucosa/metabolismo , Glucólisis/genética , Glucólisis/fisiología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Metástasis de la Neoplasia/genética , Consumo de Oxígeno/genética , Consumo de Oxígeno/fisiología
16.
Breast Cancer Res ; 15(1): 305, 2013 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-23448381

RESUMEN

Transforming growth factor beta (TGF-ß) has received noteworthy attention in the recent past due to its unique characteristic of functionally switching roles from tumor suppressor to metastasis promoter. To uncover the black box surrounding the mechanisms of TGF-ß, Taylor and colleagues performed global miRNA expression analyses using a murine mammary carcinoma progression model. They discovered multiple miRNA regulated by TGF-ß and matrix stiffness. Focusing on miR-181a, they uncovered an intricate pathway regulating breast cancer metastasis that sheds new insight into metastasis regulation that may prove useful in clinical settings.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias Mamarias Animales/genética , MicroARNs/biosíntesis , Factor de Crecimiento Transformador beta/genética , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Mamarias Animales/patología , Ratones , Factor de Crecimiento Transformador beta/biosíntesis
17.
PLoS One ; 8(2): e55966, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23390556

RESUMEN

Breast cancer metastasis suppressor 1 (BRMS1) is a predominantly nuclear protein that suppresses metastasis in multiple human and murine carcinoma cell lines. BRMS1 interacts with several nuclear proteins including SIN3:HDAC chromatin remodeling complexes that are involved in repressing transcription. However, recent reports suggest BRMS1 may function in the cytoplasm. BRMS1 has two predicted nuclear localization sequences (NLS) that are located near the C-terminus (amino acids 198-205 and 238-244, NLS1 and NLS2 respectively). We hypothesized that nuclear localization sequences of BRMS1 were essential for BRMS1 mediated metastasis suppression. Replacement of NLS2 with NLS1 (BRMS1(NLS1,1)), truncation at 238 (BRMS1(ΔNLS2)), or switching the location of NLS1 and NLS2 (BRMS1(NLS2,1)) did not affect nuclear localization; but, replacement of NLS1 with NLS2 (BRMS1(NLS2,2)) or truncation at 197 (BRMS1(ΔNLS) which removes both NLS) promoted cytoplasmic localization. MDA-MB-231 human metastatic breast cancer cells transduced with BRMS1(NLS1,1), BRMS1(NLS2,2) or BRMS1(NLS2,1) were evaluated for metastasis suppression in an experimental xenograft mouse model. Interestingly, while NLS2 was not necessary for nuclear localization, it was found to be important for metastasis suppression since BRMS1(NLS2,2) suppressed metastasis by 85%. In contrast, BRMS1(NLS2,1) and BRMS1(NLS1,1) did not significantly suppress metastasis. Both BRMS1 and BRMS1(NLS2,2) co-immunoprecipitated with SIN3A in the nucleus and cytoplasm; however, BRMS1(NLS1,1) and BRMS1(NLS2,1) were associated with SIN3A in the nucleus only. Moreover, BRMS1 and BRMS1(NLS2,2), but not BRMS1(NLS1,1) and BRMS1(NLS2,1), down-regulated the pro-metastatic microRNA, miR-10b. Together, these data demonstrate an important role for NLS2 in the cytoplasm that is critical for metastasis suppression and is distinct from nuclear localization.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Señales de Localización Nuclear/genética , Animales , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Femenino , Humanos , Ratones , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Mutación , Proteínas de Neoplasias/química , Señales de Localización Nuclear/química , Proteínas Nucleares/química , Proteínas Nucleares/genética , Unión Proteica , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Complejo Correpresor Histona Desacetilasa y Sin3 , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Cancer Metastasis Rev ; 31(3-4): 641-51, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22678236

RESUMEN

Epigenetic regulation of gene transcription by histone modification and chromatin remodeling has been linked to many biological and pathological events including cancer metastasis. Breast cancer metastasis suppressor 1 (BRMS1) interacts with SIN3 chromatin remodeling complexes, and, upon forced expression in metastatic cells, a nearly complete suppression of metastasis is noted without preventing primary tumor growth. The data for BRMS1-mediated metastasis suppression and SIN3 interaction are clear; however, connecting the inhibition directly to the association of BRMS1 with SIN3 complexes is currently not well defined. Considering the recent advancements in developing epigenetic drugs for cancer therapy, an improved understanding of how the interactions between BRMS1 and SIN3 regulate the process of metastasis should lead to novel therapies specifically targeting the most deadly aspect of tumor progression. In this article, the data for BRMS1-mediated metastasis suppression are reviewed with a focus on how the SIN3 chromatin remodeling complexes may be functionally involved.


Asunto(s)
Ensamble y Desensamble de Cromatina , Metástasis de la Neoplasia/prevención & control , Proteínas de Neoplasias/fisiología , Complejo Correpresor Histona Desacetilasa y Sin3/fisiología , Proteínas Supresoras de Tumor/fisiología , Animales , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Proteínas de Neoplasias/genética , Proteínas Represoras
20.
Clin Exp Metastasis ; 29(4): 315-25, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22241150

RESUMEN

Morbidity and mortality of breast cancer patients are drastically increased when primary tumor cells are able to spread to distant sites and proliferate to become secondary lesions. Effective treatment of metastatic disease has been limited; therefore, an increased molecular understanding to identify biomarkers and therapeutic targets is needed. Breast cancer metastasis suppressor 1 (BRMS1) suppresses development of pulmonary metastases when expressed in a variety of cancer types, including metastatic mammary carcinoma. Little is known of Brms1 function throughout the initiation and progression of mammary carcinoma. The goal of this study was to investigate mechanisms of Brms1-mediated metastasis suppression in transgenic mice that express Brms1 using polyoma middle T oncogene-induced models. Brms1 expression did not significantly alter growth of the primary tumors. When expressed ubiquitously using a ß-actin promoter, Brms1 suppressed pulmonary metastasis and promoted apoptosis of tumor cells located in the lungs but not in the mammary glands. Surprisingly, selective expression of Brms1 in the mammary gland using the MMTV promoter did not significantly block metastasis nor did it promote apoptosis in the mammary glands or lung, despite MMTV-induced expression within the lungs. These results strongly suggest that cell type-specific over-expression of Brms1 is important for Brms1-mediated metastasis suppression.


Asunto(s)
Apoptosis/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/patología , Metástasis de la Neoplasia/genética , Proteínas Represoras/genética , Animales , Femenino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Metástasis de la Neoplasia/patología , Regiones Promotoras Genéticas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
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