RESUMO
The burden of cancer in the United States is unevenly spread across its different populations, with stark differences in both disease prevalence and outcome on the basis of race and ethnicity. Although a large portion of these differences can be explained by a variety of sociobehavioral and socioeconomic factors, even after these exposures are taken into consideration, considerable disparities persist. In this review, we explore a conceptual framework of biological theories and unifying concepts, based on an evolutionary perspective, that may help better define common guiding principles for exploration of underlying causes of cancer health disparities. The ultimate goal of this conceptual perspective is to outline approaches that may aid in establishing integrated pathway and processes analyses to provide useful insights to guide the development of future interventions. These interventions will improve outcome, increase prevention, and ultimately eliminate all disparities.
Assuntos
Disparidades nos Níveis de Saúde , Neoplasias/etnologia , Alostase/genética , Evolução Biológica , Humanos , Incidência , Neoplasias/patologia , Neoplasias/fisiopatologia , Estados Unidos/epidemiologia , Cicatrização/fisiologiaRESUMO
PURPOSE: Triple-negative breast cancer (TNBC) is most prevalent in young women of African ancestry (WAA) compared to women of other ethnicities. Recent studies found a correlation between high expression of the transcription factor Kaiso, TNBC aggressiveness, and ethnicity. However, little is known about Kaiso expression and localization patterns in TNBC tissues of WAA. Herein, we analyze Kaiso expression patterns in TNBC tissues of African (Nigerian), Caribbean (Barbados), African American (AA), and Caucasian American (CA) women. METHODS: Formalin-fixed and paraffin embedded (FFPE) TNBC tissue blocks from Nigeria and Barbados were utilized to construct a Nigerian/Barbadian tissue microarray (NB-TMA). This NB-TMA and a commercially available TMA comprising AA and CA TNBC tissues (AA-CA-YTMA) were subjected to immunohistochemistry to assess Kaiso expression and subcellular localization patterns, and correlate Kaiso expression with TNBC clinical features. RESULTS: Nigerian and Barbadian women in our study were diagnosed with TNBC at a younger age than AA and CA women. Nuclear and cytoplasmic Kaiso expression was observed in all tissues analyzed. Analysis of Kaiso expression in the NB-TMA and AA-CA-YTMA revealed that nuclear Kaiso H scores were significantly higher in Nigerian, Barbadian, and AA women compared with CA women. However, there was no statistically significant difference in nuclear Kaiso expression between Nigerian versus Barbadian women, or Barbadian versus AA women. CONCLUSIONS: High levels of nuclear Kaiso expression were detected in patients with a higher degree of African heritage compared to their Caucasian counterparts, suggesting a role for Kaiso in TNBC racial disparity.
Assuntos
Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Barbados , Etnicidade , Feminino , Humanos , Pessoa de Meia-Idade , Nigéria , Neoplasias de Mama Triplo Negativas/etnologiaRESUMO
The eleven-nineteen lysine-rich leukemia protein (ELL) is a key regulator of RNA polymerase II mediated transcription. ELL facilitates RNA polymerase II transcription pause site entry and release by dynamically interacting with p300 and the positive transcription elongation factor b (P-TEFb). In this study, we investigated the role of ELL during the HTLV-1 Tax oncogene induced transactivation. We show that ectopic expression of Tax enhances ELL incorporation into p300 and P-TEFb containing transcriptional complexes and the subsequent recruitment of these complexes to target genes in vivo. Depletion of ELL abrogates Tax induced transactivation of the immediate early genes Fos, Egr2 and NF-kB, suggesting that ELL is an essential cellular cofactor of the Tax oncogene. Thus, our study identifies a novel mechanism of ELL-dependent transactivation of immediate early genes by Tax and provides the rational for further defining the genome-wide targets of Tax and ELL.
Assuntos
Proteína p300 Associada a E1A/genética , Produtos do Gene tax/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Fator B de Elongação Transcricional Positiva/genética , Ativação Transcricional , Fatores de Elongação da Transcrição/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Proteína p300 Associada a E1A/metabolismo , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Regulação da Expressão Gênica , Produtos do Gene tax/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Células Jurkat , NF-kappa B/genética , NF-kappa B/metabolismo , Fator B de Elongação Transcricional Positiva/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Fatores de Elongação da Transcrição/antagonistas & inibidores , Fatores de Elongação da Transcrição/metabolismoRESUMO
There has been an explosion of articles on epithelial-mesenchymal transition and other modes of cellular reprogramming that influence the tumor microenvironment. Many controversies exist and remain to be resolved. The interest of the pathologists in the molecular and functional parallels between wound healing and the developing tumor stroma has its earliest origin in the writings of Rudolph Virchow in the 19(th) century. Since then, most of the focus has been primarily on the dynamics of the extracellular matrix; however, new interest has been redirected toward deciphering and understanding the enigmatic, yet elegant, plasticity of the cellular components of the proliferating epithelia and stroma and how they are reciprocally influenced. Citing several examples from breast cancer research, we will trace how these perspectives have unfolded in the pages of The American Journal of Pathology and other investigative journals during the past century, their impact, and where the field is headed.
Assuntos
Reprogramação Celular/genética , Neoplasias/genética , Neoplasias/patologia , Cicatrização , Animais , Epigênese Genética , Humanos , Miofibroblastos/patologia , Microambiente Tumoral/genéticaRESUMO
Detection of cell-free circulating tumor DNA (ctDNA) from solid tumors is a fast-evolving field with significant potential for improving patient treatment outcomes. The spectrum of applications for ctDNA assays is broad and includes very diverse intended uses that will require different strategies to demonstrate utility. On September 14-15, 2023, the National Cancer Institute held an in-person workshop in Rockville, MD entitled "ctDNA in Cancer Treatment and Clinical Care". The goal of the workshop was to examine what is currently known and what needs to be determined for various ctDNA liquid biopsy use cases related to treatment and management of patients with solid tumors and to explore how the community can best assess the value of ctDNA assays and technology. Additionally, new approaches were presented that may show promise in the future. The information exchanged in this workshop will provide the community with a better understanding of this field and its potential to affect and benefit decision-making in the treatment of patients with solid tumors.
RESUMO
BACKGROUND: Precision medicine has become a mainstay of cancer care in recent years. The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program has been an authoritative source of cancer statistics and data since 1973. However, tumor genomic information has not been adequately captured in the cancer surveillance data, which impedes population-based research on molecular subtypes. To address this, the SEER Program has developed and implemented a centralized process to link SEER registries' tumor cases with genomic test results that are provided by molecular laboratories to the registries. METHODS: Data linkages were carried out following operating procedures for centralized linkages established by the SEER Program. The linkages used Match*Pro, a probabilistic linkage software, and were facilitated by the registries' trusted third party (an honest broker). The SEER registries provide to NCI limited datasets that undergo preliminary evaluation prior to their release to the research community. RESULTS: Recently conducted genomic linkages included OncotypeDX Breast Recurrence Score, OncotypeDX Breast Ductal Carcinoma in Situ, OncotypeDX Genomic Prostate Score, Decipher Prostate Genomic Classifier, DecisionDX Uveal Melanoma, DecisionDX Preferentially Expressed Antigen in Melanoma, DecisionDX Melanoma, and germline tests results in Georgia and California SEER registries. CONCLUSIONS: The linkages of cancer cases from SEER registries with genomic test results obtained from molecular laboratories offer an effective approach for data collection in cancer surveillance. By providing de-identified data to the research community, the NCI's SEER Program enables scientists to investigate numerous research inquiries.
Assuntos
Genômica , Neoplasias , Sistema de Registros , Programa de SEER , Humanos , Programa de SEER/estatística & dados numéricos , Estados Unidos/epidemiologia , Neoplasias/genética , Neoplasias/epidemiologia , Neoplasias/diagnóstico , Genômica/métodos , Sistema de Registros/estatística & dados numéricos , Feminino , Masculino , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Registro Médico Coordenado/métodos , National Cancer Institute (U.S.)RESUMO
The sequencing of the human genome led to many insights into gene organization and structure. One interesting observation was the high frequency of bidirectional promoters characterized by two protein encoding genes whose promoters are arranged in a divergent or "head-to-head" configuration with less than 2000 base pairs of intervening sequence. Computational estimates published by various groups indicate that nearly 10% of the coding gene promoters are arranged in such a manner and the extent of this bias is a unique feature of mammalian genomes. Moreover, as a class, head-to-head promoters appear to be enriched in specific categories of gene function. Here we review the structure, composition, genomic properties and functional classifications of genes controlled by bidirectional promoters and explore the biological implication of these features. This article is part of a Special Issue entitled: Chromatin in time and space.
Assuntos
Regiões Promotoras Genéticas , Sequência de Bases , Cromatina/genética , Cromatina/metabolismo , Sequência Consenso , Regulação da Expressão Gênica , Humanos , Ligação Proteica , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia , Transcrição GênicaRESUMO
Diabetes commonly affects patients with cancer. We investigated the influence of diabetes on breast cancer biology using a 3-pronged approach that included analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. We aimed to identify shared phenotypes and molecular signatures by investigating the metabolome, transcriptome, and tumor mutational burden. Diabetes and hyperglycemia did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. They also promoted oxyradical formation and both a transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tended to accumulate in breast tumors in the presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, we conclude that diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors.
Assuntos
Neoplasias da Mama , Diabetes Mellitus , Hiperglicemia , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Dano ao DNA , Reparo do DNARESUMO
Women of African descent have the highest breast cancer mortality in the United States and are more likely than women from other population groups to develop an aggressive disease. It remains uncertain to what extent breast cancer in Africa is reminiscent of breast cancer in African American or European American patients. Here, we performed whole-exome sequencing of genomic DNA from 191 breast tumor and non-cancerous adjacent tissue pairs obtained from 97 African American, 69 European American, 2 Asian American, and 23 Kenyan patients. Our analysis of the sequencing data revealed an elevated tumor mutational burden in both Kenyan and African American patients, when compared with European American patients. TP53 mutations were most prevalent, particularly in African American patients, followed by PIK3CA mutations, which showed similar frequencies in European American, African American, and the Kenyan patients. Mutations targeting TBX3 were confined to European Americans and those targeting the FBXW7 tumor suppressor to African American patients whereas mutations in the ARID1A gene that are known to confer resistance to endocrine therapy were distinctively enriched among Kenyan patients. A Kyoto Encyclopedia of Genes and Genomes pathway analysis could link FBXW7 mutations to an increased mitochondrial oxidative phosphorylation capacity in tumors carrying these mutations. Finally, Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures in tumors correlated with the occurrence of driver mutations, immune cell profiles, and neighborhood deprivation with associations ranging from being mostly modest to occasionally robust. To conclude, we found mutational profiles that were different between these patient groups. The differences concentrated among genes with low mutation frequencies in breast cancer. SIGNIFICANCE: The study describes differences in tumor mutational profiles between African American, European American, and Kenyan breast cancer patients. It also investigates how these profiles may relate to the tumor immune environment and the neighborhood environment in which the patients had residence. Finally, it describes an overrepresentation of ARID1A gene mutations in breast tumors of the Kenyan patients.
Assuntos
Negro ou Afro-Americano , Neoplasias da Mama , Feminino , Humanos , Negro ou Afro-Americano/genética , Neoplasias da Mama/genética , Proteína 7 com Repetições F-Box-WD/genética , Quênia , Mutação , Estados Unidos , Brancos/genética , População Negra/genética , Asiático/genéticaRESUMO
Profiling the dynamic interaction of p300 with proximal promoters of human T cells identified a class of genes that rapidly coassemble p300 and RNA polymerase II (pol II) following mitogen stimulation. Several of these p300 targets are immediate early genes, including FOS, implicating a prominent role for p300 in the control of primary genetic responses. The recruitment of p300 and pol II rapidly transitions to the assembly of several elongation factors, including the positive transcriptional elongation factor (P-TEFb), the bromodomain-containing protein (BRD4), and the elongin-like eleven nineteen lysine-rich leukemia protein (ELL). However, transcription at many of these rapidly induced genes is transient, wherein swift departure of P-TEFb, BRD4, and ELL coincides with termination of transcriptional elongation. Unexpectedly, both p300 and pol II remain accumulated or "bookmarked" at the proximal promoter long after transcription has terminated, demarking a clear mechanistic separation between the recruitment and elongation phases of transcription in vivo. The bookmarked pol II is depleted of both serine-2 and serine-5 phosphorylation of its C-terminal domain and remains proximally positioned at the promoter for hours. Surprisingly, these p300/pol II bookmarked genes can be readily reactivated, and elongation factors can be reassembled by subsequent addition of nonmitogenic agents that, alone, have minimal effects on transcription in the absence of prior preconditioning by mitogen stimulation. These findings suggest that p300 is likely to play an important role in biological processes in which transcriptional bookmarking or preconditioning influences cellular growth and development through the dynamic priming of genes for response to rechallenge by secondary stimuli.
Assuntos
Proteína p300 Associada a E1A/metabolismo , Regulação da Expressão Gênica , RNA Polimerase II/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linhagem Celular , Estudo de Associação Genômica Ampla , Humanos , Memória Imunológica/genética , Mitógenos/farmacologia , Regiões Promotoras Genéticas , Subpopulações de Linfócitos T/efeitos dos fármacos , Transcrição Gênica , Fatores de Elongação da Transcrição/metabolismoRESUMO
Women of African ancestry suffer higher rates of breast cancer mortality compared with all other groups in the United States. Though the precise reasons for these disparities remain unclear, many recent studies have implicated a role for differences in tumor biology. Using an epitope-validated antibody against the endoplasmic reticulum-associated E3 ligase, gp78, we show that elevated levels of gp78 in patient breast cancer cells predict poor survival. Moreover, high levels of gp78 are associated with poor outcomes in both ER+ and ER- tumors, and breast cancers expressing elevated amounts of gp78 protein are enriched in gene expression pathways that influence cell cycle, metabolism, receptor-mediated signaling, and cell stress response pathways. In multivariate analysis adjusted for subtype and grade, gp78 protein is an independent predictor of poor outcomes in women of African ancestry. Furthermore, gene expression signatures, derived from patients stratified by gp78 protein expression, are strong predictors of recurrence and pathological complete response in retrospective clinical trial data and share many common features with gene sets previously identified to be overrepresented in breast cancers based on race. These findings implicate a prominent role for gp78 in tumor progression and offer insights into our understanding of racial differences in breast cancer outcomes.
Assuntos
Neoplasias da Mama , Ubiquitina-Proteína Ligases , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Retículo Endoplasmático/metabolismo , Feminino , Humanos , Estudos Retrospectivos , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismoRESUMO
The use of digital pathology for the histomorphologic profiling of pathological specimens is expanding the precision and specificity of quantitative tissue analysis at an unprecedented scale; thus, enabling the discovery of new and functionally relevant histological features of both predictive and prognostic significance. In this study, we apply quantitative automated image processing and computational methods to profile the subcellular distribution of the multi-functional transcriptional regulator, Kaiso (ZBTB33), in the tumors of a large racially diverse breast cancer cohort from a designated health disparities region in the United States. Multiplex multivariate analysis of the association of Kaiso's subcellular distribution with other breast cancer biomarkers reveals novel functional and predictive linkages between Kaiso and the autophagy-related proteins, LC3A/B, that are associated with features of the tumor immune microenvironment, survival, and race. These findings identify effective modalities of Kaiso biomarker assessment and uncover unanticipated insights into Kaiso's role in breast cancer progression.
Assuntos
Neoplasias da Mama/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Fatores de Transcrição/metabolismo , Microambiente Tumoral , Automação Laboratorial , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Imunofluorescência , Regulação Neoplásica da Expressão Gênica , Humanos , Interpretação de Imagem Assistida por Computador , Microscopia de Fluorescência , Proteínas Associadas aos Microtúbulos/genética , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Transdução de Sinais , Fatores de Tempo , Análise Serial de Tecidos , Fatores de Transcrição/genética , Evasão Tumoral , Estados Unidos/epidemiologiaRESUMO
Induced pluripotent stem cells (iPSCs) can be derived from differentiated cells, enabling the generation of personalized disease models by differentiating patient-derived iPSCs into disease-relevant cell lines. While genetic variability between different iPSC lines affects differentiation potential, how this variability in somatic cells affects pluripotent potential is less understood. We generated and compared transcriptomic data from 72 dermal fibroblast-iPSC pairs with consistent variation in reprogramming efficiency. By considering equal numbers of samples from self-reported African Americans and White Americans, we identified both ancestry-dependent and ancestry-independent transcripts associated with reprogramming efficiency, suggesting that transcriptomic heterogeneity can substantially affect reprogramming. Moreover, reprogramming efficiency-associated genes are involved in diverse dynamic biological processes, including cancer and wound healing, and are predictive of 5-year breast cancer survival in an independent cohort. Candidate genes may provide insight into mechanisms of ancestry-dependent regulation of cell fate transitions and motivate additional studies for improvement of reprogramming.
Assuntos
Fenômenos Biológicos , Células-Tronco Pluripotentes Induzidas , Diferenciação Celular/genética , Linhagem Celular , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , TranscriptomaRESUMO
INTRODUCTION: Lung cancer incidence is higher among African Americans (AAs) compared with European Americans (EAs) in the United States, especially among men. Although significant progress has been made profiling the genomic makeup of lung cancer in EAs, AAs continue to be underrepresented. Our objective was to chart the genome-wide landscape of somatic mutations in lung cancer tumors from AAs. METHODS: In this study, we used the whole-exome sequencing of 82 tumor and noninvolved tissue pairs from AAs. Patients were selected from an ongoing case-control study conducted by the National Cancer Institute and the University of Maryland. RESULTS: Among all samples, we identified 178 significantly mutated genes (p < 0.05), five of which passed the threshold for false discovery rate (p < 0.1). In lung adenocarcinoma (LUAD) tumors, mutation rates in STK11 (p = 0.05) and RB1 (p = 0.008) were significantly higher in AA LUAD tumors (25% and 13%, respectively) compared with The Cancer Genome Atlas EA samples (14% and 4%, respectively). In squamous cell carcinomas, mutation rates in STK11 (p = 0.002) were significantly higher among AA (8%) than EA tumors from The Cancer Genome Atlas (1%). Integrated somatic mutation data with CIBERSORT (Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts) data analysis revealed LUAD tumors from AAs carrying STK11 mutations have decreased interferon signaling. CONCLUSIONS: Although a considerable degree of the somatic mutation landscape is shared between EAs and AAs, discrete differences in mutation frequency in potentially important oncogenes and tumor suppressors exist. A better understanding of the molecular basis of lung cancer in AA patients and leveraging this information to guide clinical interventions may help reduce disparities.
Assuntos
Negro ou Afro-Americano , Neoplasias Pulmonares , Negro ou Afro-Americano/genética , Idoso , Estudos de Casos e Controles , Exoma/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Estados Unidos , Sequenciamento do ExomaRESUMO
PURPOSE: Compared with their European American (EA) counterparts, African American (AA) women are more likely to die from breast cancer in the United States. This disparity is greatest in hormone receptor-positive subtypes. Here we uncover biological factors underlying this disparity by comparing functional expression and prognostic significance of master transcriptional regulators of luminal differentiation. EXPERIMENTAL DESIGN: Data and biospecimens from 262 AA and 293 EA patients diagnosed with breast cancer from 2001 to 2010 at a major medical center were analyzed by IHC for functional biomarkers of luminal differentiation, including estrogen receptor (ESR1) and its pioneer factors, FOXA1 and GATA3. Integrated comparison of protein levels with network-level gene expression analysis uncovered predictive correlations with race and survival. RESULTS: Univariate or multivariate HRs for overall survival, estimated from digital IHC scoring of nuclear antigen, show distinct differences in the magnitude and significance of these biomarkers to predict survival based on race: ESR1 [EA HR = 0.47; 95% confidence interval (CI), 0.31-0.72 and AA HR = 0.77; 95% CI, 0.48-1.18]; FOXA1 (EA HR = 0.38; 95% CI, 0.23-0.63 and AA HR = 0.53; 95% CI, 0.31-0.88), and GATA3 (EA HR = 0.36; 95% CI, 0.23-0.56; AA HR = 0.57; CI, 0.56-1.4). In addition, we identify genes in the downstream regulons of these biomarkers highly correlated with race and survival. CONCLUSIONS: Even within clinically homogeneous tumor groups, regulatory networks that drive mammary luminal differentiation reveal race-specific differences in their association with clinical outcome. Understanding these biomarkers and their downstream regulons will elucidate the intrinsic mechanisms that drive racial disparities in breast cancer survival.
Assuntos
População Negra/genética , Neoplasias da Mama/mortalidade , Receptor alfa de Estrogênio/metabolismo , Fator de Transcrição GATA3/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator 3-alfa Nuclear de Hepatócito/metabolismo , População Branca/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/etnologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Disparidades nos Níveis de Saúde , Humanos , Imuno-Histoquímica/métodos , Pessoa de Meia-Idade , Taxa de Sobrevida , Estados UnidosRESUMO
The C-terminal binding protein (CtBP) is an NADH-dependent dimeric family of nuclear proteins that scaffold interactions between transcriptional regulators and chromatin-modifying complexes. Its association with poor survival in several cancers implicates CtBP as a promising target for pharmacological intervention. We employed computer-assisted drug design to search for CtBP inhibitors, using quantitative structure-activity relationship (QSAR) modeling and docking. Functional screening of these drugs identified 4 compounds with low toxicity and high water solubility. Micro molar concentrations of these CtBP inhibitors produces significant de-repression of epigenetically silenced pro-epithelial genes, preferentially in the triple-negative breast cancer cell line MDA-MB-231. This epigenetic reprogramming occurs through eviction of CtBP from gene promoters; disrupted recruitment of chromatin-modifying protein complexes containing LSD1, and HDAC1; and re-wiring of activating histone marks at targeted genes. In functional assays, CtBP inhibition disrupts CtBP dimerization, decreases cell migration, abolishes cellular invasion, and improves DNA repair. Combinatorial use of CtBP inhibitors with the LSD1 inhibitor pargyline has synergistic influence. Finally, integrated correlation of gene expression in breast cancer patients with nuclear levels of CtBP1 and LSD1, reveals new potential therapeutic vulnerabilities. These findings implicate a broad role for this class of compounds in strategies for epigenetically targeted therapeutic intervention.
Assuntos
Oxirredutases do Álcool/genética , Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética/genética , Feminino , HumanosRESUMO
2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) is a member of a recently identified class of redox-reactive thalidomide analogs that show selective killing of leukemic cells by increasing intracellular reactive oxygen species (ROS) and targeting multiple transcriptional pathways. Flavopiridol is a semisynthetic flavonoid that inhibits cyclin-dependent kinases and also shows selective lethality against leukemic cells. The purpose of this study is to explore the efficacy and mechanism of action of the combinatorial use of the redox-reactive thalidomide CPS49 and the cyclin-dependent kinase inhibitor flavopiridol as a selective antileukemic therapeutic strategy. In combination, CPS49 and flavopiridol were found to induce selective cytotoxicity associated with mitochondrial dysfunction and elevations of ROS in leukemic cells ranging from additive to synergistic activity at low micromolar concentrations. Highest synergy was observed at the level of ROS generation with a strong correlation between cell-specific cytotoxicity and reciprocal coupling of drug-induced ROS elevation with glutathione depletion. Examination of the transcriptional targeting of CPS49 and flavopiridol combinations reveals that the drugs act in concert to initiate a cell specific transcriptional program that manipulates nuclear factor-kappaB (NF-kappaB), E2F-1, and p73 activity to promote enhanced mitochondrial instability by simultaneously elevating the expression of the proapoptotic factors BAX, BAD, p73, and PUMA while depressing expression of the antiapoptotic genes MCL1, XIAP, BCL-xL, SURVIVIN, and MDM2. The coadministration of CPS49 and flavopiridol acts through coordinate targeting of transcriptional pathways that enforce selective mitochondrial dysfunction and ROS elevation and is therefore a promising new therapeutic combination that warrants further preclinical exploration.
Assuntos
Antineoplásicos/farmacologia , Flavonoides/farmacologia , Homeostase/efeitos dos fármacos , Leucemia/patologia , Mitocôndrias/efeitos dos fármacos , Piperidinas/farmacologia , Talidomida/análogos & derivados , Proteínas Reguladoras de Apoptose/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Sequestradores de Radicais Livres/farmacologia , Glutationa/metabolismo , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Especificidade de Órgãos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Talidomida/farmacologia , Transcrição Gênica/efeitos dos fármacos , Proteínas Supressoras de Tumor/metabolismoRESUMO
A central hallmark of epigenetic inheritance is the parental transmission of changes in patterns of gene expression to progeny without modification of DNA sequence. Although, the trans-generational conveyance of this molecular memory has been traditionally linked to covalent modification of histone and/or DNA, recent studies suggest a role for proteins that persist or remain bound within chromatin to "bookmark" specific loci for enhanced or potentiated responses in daughter cells immediately following cell division. In this report we describe a role for p300 in enabling gene bookmarking by pre-initiation complexes (PICs) containing RNA polymerase II (pol II), Mediator and TBP. Once formed these complexes require p300 to enable reacquisition of protein complex assemblies, chromatin modifications and long range chromatin interactions that facilitate post-mitotic transmission of transcriptional memory of prior environmental stimuli.
Assuntos
Proteína p300 Associada a E1A/genética , Epigênese Genética , Padrões de Herança , Regiões Promotoras Genéticas , Transcrição Gênica , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Cromatina/química , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteína p300 Associada a E1A/deficiência , Técnicas de Inativação de Genes , Células HCT116 , Histonas/genética , Histonas/metabolismo , Humanos , Células Jurkat , Complexo Mediador/genética , Complexo Mediador/metabolismo , Mitose , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Ligação Proteica , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Transdução de Sinais , Proteína de Ligação a TATA-Box/genética , Proteína de Ligação a TATA-Box/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , CoesinasRESUMO
The prevalence of obesity has given rise to significant global concerns as numerous population-based studies demonstrate an incontrovertible association between obesity and breast cancer. Mechanisms proposed to account for this linkage include exaggerated levels of carbohydrate substrates, elevated levels of circulating mitogenic hormones, and inflammatory cytokines that impinge on epithelial programming in many tissues. Moreover, recently many scientists have rediscovered the observation, first described by Otto Warburg nearly a century ago, that most cancer cells undergo a dramatic metabolic shift in energy utilization and expenditure that fuels and supports the cellular expansion associated with malignant proliferation. This shift in substrate oxidation comes at the cost of sharp changes in the levels of the high energy intermediate, nicotinamide adenine dinucleotide (NADH). In this review, we discuss a novel example of how shifts in the concentration and flux of substrates metabolized and generated during carbohydrate metabolism represent components of a signaling network that can influence epigenetic regulatory events in the nucleus. We refer to this regulatory process as "metabolic transduction" and describe how the C-terminal binding protein (CtBP) family of NADH-dependent nuclear regulators represents a primary example of how cellular metabolic status can influence epigenetic control of cellular function and fate.
RESUMO
The C-terminal binding protein (CtBP) is a NADH-dependent transcriptional repressor that links carbohydrate metabolism to epigenetic regulation by recruiting diverse histone-modifying complexes to chromatin. Here global profiling of CtBP in breast cancer cells reveals that it drives epithelial-to-mesenchymal transition, stem cell pathways and genome instability. CtBP expression induces mesenchymal and stem cell-like features, whereas CtBP depletion or caloric restriction reverses gene repression and increases DNA repair. Multiple members of the CtBP-targeted gene network are selectively downregulated in aggressive breast cancer subtypes. Differential expression of CtBP-targeted genes predicts poor clinical outcome in breast cancer patients, and elevated levels of CtBP in patient tumours predict shorter median survival. Finally, both CtBP promoter targeting and gene repression can be reversed by small molecule inhibition. These findings define broad roles for CtBP in breast cancer biology and suggest novel chromatin-based strategies for pharmacologic and metabolic intervention in cancer.