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1.
Cancers (Basel) ; 13(19)2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34638504

RESUMO

Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate the NEPC phenotype remains largely elusive. The unbiased differential miR expression profiling of human PCa cells genetically modulated for TBX2 expression led to the identification of miR-200c-3p. Our findings have unraveled the TBX2/miR-200c-3p/SOX2/N-MYC signaling axis in NEPC transdifferentiation. Mechanistically, we found that: (1) TBX2 binds to the promoter and represses the expression of miR-200c-3p, a miR reported to be lost in castrate resistant prostate cancer (CRPC), and (2) the repression of miR-200c-3p results in the increased expression of its targets SOX2 and N-MYC. In addition, the rescue of mir-200c-3p in the context of TBX2 blockade revealed that miR-200c-3p is the critical intermediary effector in TBX2 regulation of SOX2 and N-MYC. Further, our studies show that in addition to the intracellular mode, TBX2/miR-200c-3p/SOX2/N-MYC signaling can promote NEPC transdifferentiation via exosome-mediated intercellular mechanism, an increasingly recognized and key mode of propagation of the NEPC phenotype.

2.
Front Oncol ; 11: 710337, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34350123

RESUMO

Background: Increased expression of the progesterone receptor membrane component 1, a heme and progesterone binding protein, is frequently found in triple negative breast cancer tissue. The basis for the expression of PGRMC1 and its regulation on cellular signaling mechanisms remain largely unknown. Therefore, we aim to study microRNAs that target selective genes and mechanisms that are regulated by PGRMC1 in TNBCs. Methods: To identify altered miRNAs, whole human miRNome profiling was performed following AG-205 treatment and PGRMC1 silencing. Network analysis identified miRNA target genes while KEGG, REACTOME and Gene ontology were used to explore altered signaling pathways, biological processes, and molecular functions. Results: KEGG term pathway analysis revealed that upregulated miRNAs target specific genes that are involved in signaling pathways that play a major role in carcinogenesis. While multiple downregulated miRNAs are known oncogenes and have been previously demonstrated to be overexpressed in a variety of cancers. Overlapping miRNA target genes associated with KEGG term pathways were identified and overexpression/amplification of these genes was observed in invasive breast carcinoma tissue from TCGA. Further, the top two genes (CCND1 and YWHAZ) which are highly genetically altered are also associated with poorer overall survival. Conclusions: Thus, our data demonstrates that therapeutic targeting of PGRMC1 in aggressive breast cancers leads to the activation of miRNAs that target overexpressed genes and deactivation of miRNAs that have oncogenic potential.

3.
Front Oncol ; 11: 635237, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34168978

RESUMO

Metaplastic breast cancer is a rare and often chemo-refractory subtype of breast cancer with poor prognosis and limited treatment options. Recent studies have reported overexpression of programmed death ligand 1 (PD-L1) in metaplastic breast cancers, and there are several reports of anti-PD-1/L1 being potentially active in this disease. In this case series, we present 5 patients with metastatic metaplastic breast cancer treated with anti-PD-1-based therapy at a single center, with 3 of 5 cases demonstrating a response to therapy, and one of the responding cases being a metaplastic lobular carcinoma with low-level hormone receptor expression. Cases were evaluated for PD-L1 expression, tumor infiltrating lymphocytes (TILs), DNA mutations, RNA sequencing, and T-cell receptor sequencing. Duration of the response in these cases was limited, in contrast to the more durable responses noted in other recently published reports.

4.
Oncoimmunology ; 10(1): 1900635, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33796412

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) has traditionally been thought of as an immunologically quiescent tumor type presumably because of a relatively low tumor mutational burden (TMB) and poor responses to checkpoint blockade therapy. However, many PDAC tumors exhibit T cell inflamed phenotypes. The presence of tertiary lymphoid structures (TLS) has recently been shown to be predictive of checkpoint blockade response in melanomas and sarcomas, and are prognostic for survival in PDAC. In order to more comprehensively understand tumor immunity in PDAC patients with TLS, we performed RNA-seq, single and multiplex IHC, flow cytometry and predictive genomic analysis on treatment naïve, PDAC surgical specimens. Forty-six percent of tumors contained distinct T and B cell aggregates reflective of "early-stage TLS" (ES-TLS), which correlated with longer overall and progression-free survival. These tumors had greater CD8+ T cell infiltration but were not defined by previously published TLS gene-expression signatures. ES-TLS+ tumors were enriched for IgG1 class-switched memory B cells and memory CD4+ T cells, suggesting durable immunological memory persisted in these patients. We also observed the presence of active germinal centers (mature-TLS) in 31% of tumors with lymphocyte clusters, whose patients had long-term survival (median 56 months). M-TLS-positive tumors had equivalent overall T cell infiltration to ES-TLS, but were enriched for activated CD4+ memory cells, naive B cells and NK cells. Finally, using a TCGA-PDAC dataset, ES-TLS+ tumors harbored a decreased TMB, but M-TLS with germinal centers expressed significantly more MHCI-restricted neoantigens as determined by an in silico neoantigen prediction method. Interestingly, M-TLS+ tumors also had evidence of increased rates of B cell somatic hypermutation, suggesting that germinal centers form in the presence of high-quality tumor neoantigens leading to increased humoral immunity that confers improved survival for PDAC patients. AbbreviationsTLS: tertiary lymphoid structures; GC: germinal center(s); PDAC: pancreatic ductal adenocarcinoma; RNA-seq: RNA sequencing; BCRseq: B cell receptor sequencing; HEV: high endothelial venule; PNAd: peripheral node addressin; TMB: tumor mutational burden; TCGA: the cancer genome atlas; PAAD: pancreatic adenocarcinoma; FFPE: formalin fixed paraffin embedded; TIME: tumor immune microenvironment.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Estruturas Linfoides Terciárias , Centro Germinativo , Humanos , Imunidade Humoral , Neoplasias Pancreáticas/genética , Sobrevivência , Microambiente Tumoral
5.
J Immunother Cancer ; 9(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33837055

RESUMO

BACKGROUND: PD-1/PD-L1 engagement and overexpression of galectin-3 (Gal-3) are critical mechanisms of tumor-induced immune suppression that contribute to immunotherapy resistance. We hypothesized that Gal-3 blockade with belapectin (GR-MD-02) plus anti-PD-1 (pembrolizumab) would enhance tumor response in patients with metastatic melanoma (MM) and head and neck squamous cell carcinoma (HNSCC). METHODS: We performed a phase I dose escalation study of belapectin+pembrolizumab in patients with advanced MM or HNSCC (NCT02575404). Belapectin was administered at 2, 4, or 8 mg/kg IV 60 min before pembrolizumab (200 mg IV every 3 weeks for five cycles). Responding patients continued pembrolizumab monotherapy for up to 17 cycles. Main eligibility requirements were a functional Eastern Cooperative Oncology Group status of 0-2, measurable or assessable disease, and no active autoimmune disease. Prior T-cell checkpoint antibody therapy was permitted. RESULTS: Objective response was observed in 50% of MM (7/14) and and 33% of HNSCC (2/6) patients. Belapectin+pembrolizumab was associated with fewer immune-mediated adverse events than anticipated with pembrolizumab monotherapy. There were no dose-limiting toxicities for belapectin within the dose range investigated. Significantly increased effector memory T-cell activation and reduced monocytic myeloid-derived suppressor cells (M-MDSCs) were observed in responders compared with non-responders. Increased baseline expression of Gal-3+ tumor cells and PD-1+CD8+ T cells in the periphery correlated with response as did higher serum trough levels of pembrolizumab. CONCLUSIONS: Belapectin+pembrolizumab therapy has activity in MM and HNSCC. Increased Gal-3 expression, expansion of effector memory T cells, and decreased M-MDSCs correlated with clinical response. Further investigation is planned.

6.
Cancer Immunol Res ; 9(6): 602-611, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33820811

RESUMO

Microsatellite-stable (MSS) colorectal cancers are characterized by low mutation burden and limited immune-cell infiltration and thereby respond poorly to immunotherapy. Here, we report a case of metastatic MSS colorectal cancer with a robust anticancer immune response. The primary tumor was resected in 2012, and the patient received several cycles of chemotherapy until 2017. In 2018, the patient underwent a left hepatectomy to remove a new metastasis. Analysis of the metastatic tumor revealed a strong CD8+ T-cell response. A high frequency of CD8+ T cells coexpressed CD39 and CD103, a phenotype characteristic of tumor-reactive cells. Using whole-exome sequencing, we identified somatic mutations that generated peptides recognized by CD39+CD103+CD8+ T cells. The observed reactivity against the tumor was dominated by the response to a single mutation that emerged in the metastasis. Somatic mutations that were not immunogenic in the primary tumor led to robust CD8+ T-cell expansion later during disease progression. Our data suggest that the cytotoxic treatment regimen received by the patient might be responsible for this effect. Hence, the capacity of cytotoxic regimens to prime the immune system in colorectal cancer patients should be investigated further and might provide a rationale for combination with immunotherapy.

7.
IEEE Comput Graph Appl ; 41(2): 8-16, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33729921

RESUMO

We argue that visualization research has overwhelmingly focused on users from the economically developed world. However, billions of people around the world are rapidly emerging as new users of information technology. Most of the next billion users of visualization technologies will come from parts of the world that are extremely populous but historically ignored by the visualization research community. Their needs may be different to the types of users that researchers have targeted in the past, but, at the same time, they may have even more to gain in terms of access to data potentially affecting their quality of life. We propose a call to action for the visualization community to identify opportunities and use cases where users can benefit from visualization; develop universal design principles; extend evaluations by including the general population; and engage with a wider global population.

8.
Nat Commun ; 12(1): 1047, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594075

RESUMO

Despite the success of checkpoint blockade in some cancer patients, there is an unmet need to improve outcomes. Targeting alternative pathways, such as costimulatory molecules (e.g. OX40, GITR, and 4-1BB), can enhance T cell immunity in tumor-bearing hosts. Here we describe the results from a phase Ib clinical trial (NCT02274155) in which 17 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) received a murine anti-human OX40 agonist antibody (MEDI6469) prior to definitive surgical resection. The primary endpoint was to determine safety and feasibility of the anti-OX40 neoadjuvant treatment. The secondary objective was to assess the effect of anti-OX40 on lymphocyte subsets in the tumor and blood. Neoadjuvant anti-OX40 was well tolerated and did not delay surgery, thus meeting the primary endpoint. Peripheral blood phenotyping data show increases in CD4+ and CD8+ T cell proliferation two weeks after anti-OX40 administration. Comparison of tumor biopsies before and after treatment reveals an increase of activated, conventional CD4+ tumor-infiltrating lymphocytes (TIL) in most patients and higher clonality by TCRß sequencing. Analyses of CD8+ TIL show increases in tumor-antigen reactive, proliferating CD103+ CD39+ cells in 25% of patients with evaluable tumor tissue (N = 4/16), all of whom remain disease-free. These data provide evidence that anti-OX40 prior to surgery is safe and can increase activation and proliferation of CD4+ and CD8+ T cells in blood and tumor. Our work suggests that increases in the tumor-reactive CD103+ CD39+ CD8+ TIL could serve as a potential biomarker of anti-OX40 clinical activity.


Assuntos
Epitopos/imunologia , Terapia Neoadjuvante , Receptores OX40/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Biópsia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Células Clonais , Intervalo Livre de Doença , Papillomavirus Humano 16/fisiologia , Humanos , Estimativa de Kaplan-Meier , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Terapia Neoadjuvante/efeitos adversos , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores OX40/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Células Estromais/metabolismo
9.
Cancer Immunol Res ; 9(4): 415-429, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33500272

RESUMO

Metabolic dysregulation is a hallmark of cancer. Many tumors exhibit auxotrophy for various amino acids, such as arginine, because they are unable to meet the demand for these amino acids through endogenous production. This vulnerability can be exploited by employing therapeutic strategies that deplete systemic arginine in order to limit the growth and survival of arginine auxotrophic tumors. Pegzilarginase, a human arginase-1 enzyme engineered to have superior stability and enzymatic activity relative to the native human arginase-1 enzyme, depletes systemic arginine by converting it to ornithine and urea. Therapeutic administration of pegzilarginase in the setting of arginine auxotrophic tumors exerts direct antitumor activity by starving the tumor of exogenous arginine. We hypothesized that in addition to this direct effect, pegzilarginase treatment indirectly augments antitumor immunity through increased antigen presentation, thus making pegzilarginase a prime candidate for combination therapy with immuno-oncology (I-O) agents. Tumor-bearing mice (CT26, MC38, and MCA-205) receiving pegzilarginase in combination with anti-PD-L1 or agonist anti-OX40 experienced significantly increased survival relative to animals receiving I-O monotherapy. Combination pegzilarginase/immunotherapy induced robust antitumor immunity characterized by increased intratumoral effector CD8+ T cells and M1 polarization of tumor-associated macrophages. Our data suggest potential mechanisms of synergy between pegzilarginase and I-O agents that include increased intratumoral MHC expression on both antigen-presenting cells and tumor cells, and increased presence of M1-like antitumor macrophages. These data support the clinical evaluation of I-O agents in conjunction with pegzilarginase for the treatment of patients with cancer.

10.
PLoS One ; 15(8): e0238380, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866185

RESUMO

Pancreatic adenocarcinoma is characterized by a complex tumor environment with a wide diversity of infiltrating stromal and immune cell types that impact the tumor response to conventional treatments. However, even in this poorly responsive tumor the extent of T cell infiltration as determined by quantitative immunohistology is a candidate prognostic factor for patient outcome. As such, even more comprehensive immunophenotyping of the tumor environment, such as immune cell type deconvolution via inference models based on gene expression profiling, holds significant promise. We hypothesized that RNA-Seq can provide a comprehensive alternative to quantitative immunohistology for immunophenotyping pancreatic cancer. We performed RNA-Seq on a prospective cohort of pancreatic tumor specimens and compared multiple approaches for gene expression-based immunophenotyping analysis compared to quantitative immunohistology. Our analyses demonstrated that while gene expression analyses provide additional information on the complexity of the tumor immune environment, they are limited in sensitivity by the low overall immune infiltrate in pancreatic cancer. As an alternative approach, we identified a set of genes that were enriched in highly T cell infiltrated pancreatic tumors, and demonstrate that these can identify patients with improved outcome in a reference population. These data demonstrate that the poor immune infiltrate in pancreatic cancer can present problems for analyses that use gene expression-based tools; however, there remains enormous potential in using these approaches to understand the relationships between diverse patterns of infiltrating cells and their impact on patient treatment outcomes.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Linfócitos T/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
11.
Br J Cancer ; 123(8): 1326-1335, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32704174

RESUMO

BACKGROUND: Increased expression of the progesterone receptor membrane component 1 (PGRMC1) has been linked to multiple cancers, including breast cancer. Despite being a regulatory receptor and a potential therapeutic target, the oncogenic potential of PGRMC1 has not been studied. METHODS: The impact of PGRMC1 on breast cancer growth and progression was studied following chemical inhibition and alteration of PGRMC1 expression, and evaluated by using online-based gene expression datasets of human breast cancer tissue. MTS, flow cytometry, qPCR, Western blotting, confocal microscopy and phosphoproteome analysis were performed. RESULTS: We observed higher PGRMC1 levels in both ER-positive ZR-75-1 and TNBC MDA-MB-468 cells. Both chemical inhibition and silencing decreased cell proliferation, induced cell-cycle arrest, promoted apoptosis and reduced the migratory and invasive capabilities of ZR-75-1 and MDA-MB-468 cells. Further, phosphoproteome analysis demonstrated an overall decrease in activation of proteins involved in PI3K/AKT/mTOR and EGFR signalling pathways. In contrast, overexpression of PGRMC1 in non-malignant MCF10A cells resulted in increased cell proliferation, and enhanced activity of PI3K/AKT/mTOR and EGFR signalling pathways. CONCLUSIONS: Our data demonstrate that PGRMC1 plays a prominent role in regulating the growth of cancer cells by altering the PI3K/AKT/mTOR and EGFR signalling mechanisms in both ER-positive and TNBC cells.


Assuntos
Neoplasias da Mama/patologia , Proteínas de Membrana/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Fosfoproteínas/metabolismo , Proteoma , Proteínas Proto-Oncogênicas c-akt/fisiologia , Receptores de Progesterona/fisiologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Receptores ErbB/fisiologia , Feminino , Humanos , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/fisiologia
12.
Clin Cancer Res ; 26(7): 1595-1605, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31831558

RESUMO

PURPOSE: To evaluate the safety and feasibility of preoperative locoregional cytokine therapy (IRX-2 regimen) in early-stage breast cancer, and to evaluate for intratumoral and peripheral immunomodulatory activity. PATIENTS AND METHODS: Sixteen patients with stage I-III early-stage breast cancer (any histology type) indicated for surgical lumpectomy or mastectomy were enrolled to receive preoperative locoregional immunotherapy with the IRX-2 cytokine biological (2 mL subcutaneous × 10 days to periareolar skin). The regimen also included single-dose cyclophosphamide (300 mg/m2) on day 1 to deplete T-regulatory cells and oral indomethacin to modulate suppressive myeloid subpopulations. The primary objective was to evaluate feasibility (i.e., receipt of therapy without surgical delays or grade 3/4 treatment-related adverse events). The secondary objective was to evaluate changes in stromal tumor-infiltrating lymphocyte score. The exploratory objective was to identify candidate pharmacodynamic changes for future study using a variety of assays, including flow cytometry, RNA and T-cell receptor DNA sequencing, and multispectral immunofluorescence. RESULTS: Preoperative locoregional cytokine administration was feasible in 100% (n = 16/16) of subjects and associated with increases in stromal tumor-infiltrating lymphocytes (P < 0.001). Programmed death ligand 1 (CD274) was upregulated at the RNA (P < 0.01) and protein level [by Ventana PD-L1 (SP142) and immunofluorescence]. Other immunomodulatory effects included upregulation of RNA signatures of T-cell activation and recruitment and cyclophosphamide-related peripheral T-regulatory cell depletion. CONCLUSIONS: IRX-2 is safe in early-stage breast cancer. Potentially favorable immunomodulatory changes were observed, supporting further study of IRX-2 in early-stage breast cancer and other malignancies.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Mama/terapia , Citocinas/uso terapêutico , Imunidade/efeitos dos fármacos , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Cuidados Pré-Operatórios , Idoso , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Segurança do Paciente , Projetos Piloto , Resultado do Tratamento
13.
Cancer Epidemiol Biomarkers Prev ; 27(6): 644-652, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29650789

RESUMO

Background: Breast tumor subtyping has failed to provide impact in susceptibility genetics. The PAM50 assay categorizes breast tumors into: Luminal A, Luminal B, HER2-enriched and Basal-like. However, tumors are often more complex than simple categorization can describe. The identification of heritable tumor characteristics has potential to decrease heterogeneity and increase power for gene finding.Methods: We used 911 sporadic breast tumors with PAM50 expression data to derive tumor dimensions using principal components (PC). Dimensions in 238 tumors from high-risk pedigrees were compared with the sporadic tumors. Proof-of-concept gene mapping, informed by tumor dimension, was performed using Shared Genomic Segment (SGS) analysis.Results: Five dimensions (PC1-5) explained the majority of the PAM50 expression variance: three captured intrinsic subtype, two were novel (PC3, PC5). All five replicated in 745 TCGA tumors. Both novel dimensions were significantly enriched in the high-risk pedigrees (intrinsic subtypes were not). SGS gene-mapping in a pedigree identified a 0.5 Mb genome-wide significant region at 12q15 This region segregated through 32 meioses to 8 breast cancer cases with extreme PC3 tumors (P = 2.6 × 10-8).Conclusions: PC analysis of PAM50 gene expression revealed multiple independent, quantitative measures of tumor diversity. These tumor dimensions show evidence for heritability and potential as powerful traits for gene mapping.Impact: Our study suggests a new approach to describe tumor expression diversity, provides new avenues for germline studies, and proposes a new breast cancer locus. Similar reparameterization of expression patterns may inform other studies attempting to model the effects of tumor heterogeneity. Cancer Epidemiol Biomarkers Prev; 27(6); 644-52. ©2018 AACR.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Cromossomos Humanos Par 12 , Feminino , Expressão Gênica , Humanos , Linhagem
14.
PLoS Genet ; 14(2): e1007111, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29389935

RESUMO

The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Reparo do DNA/genética , Mieloma Múltiplo/genética , Linhagem , Estudos de Casos e Controles , Análise Mutacional de DNA , Bases de Dados Genéticas , Família , Feminino , Predisposição Genética para Doença , Variação Genética/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Humanos , Masculino
15.
Oncotarget ; 7(50): 82538-82553, 2016 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-27769065

RESUMO

Early parity reduces the risk of breast cancer in women while nulliparity and late parity increase the risk of breast cancer. In order to translate this protection to women where early pregnancy is not feasible, much work has focused on understanding how parity confers protection against breast cancer, the molecular mechanisms by which this occurs is still not well understood. Healthy parous and nulliparous women were recruited for this study. We assessed serum protein profiles of early parous, late parous, and nulliparous women using the Phospho Explorer antibody array. Significantly altered proteins identified were validated by Western blot analysis. In silico analysis was performed with the data obtained. Our findings indicate increased phosphorylation levels of CDK1, AKT1 and Epo-R increased cell cycle and cell proliferation in late/nulliparous women. Increased levels of LIMK1, paxillin, caveolin-1, and tyrosine hydroxylase in late/nulliparous women demonstrate enhanced cell stress while decreased activity of p-p53 and pRAD51 in late/nulliparous women indicates decreased apoptosis and increased genomic instability. Further, increased levels of pFAK, pCD3zeta, pSTAT5B, MAP3K8 in early parous women favor enhanced innate/adaptive immunity. Overall, we have identified a unique protein signature that is responsible for the decreased risk of breast cancer and these proteins can also serve as biomarkers to predict the risk of breast cancer.


Assuntos
Proteínas Sanguíneas/análise , Neoplasias da Mama/prevenção & controle , Paridade , Análise Serial de Proteínas , Proteômica/métodos , Adulto , Apoptose , Biomarcadores/sangue , Western Blotting , Neoplasias da Mama/sangue , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Ciclo Celular , Proliferação de Células , Dano ao DNA , Feminino , Humanos , Pessoa de Meia-Idade , Fosforilação , Valor Preditivo dos Testes , Gravidez , Fatores de Proteção , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Transdução de Sinais
16.
Cancer Res ; 76(7): 1916-25, 2016 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-26795348

RESUMO

The findings from genome-wide association studies hold enormous potential for novel insight into disease mechanisms. A major challenge in the field is to map these low-risk association signals to their underlying functional sequence variants (FSV). Simple sequence study designs are insufficient, as the vast numbers of statistically comparable variants and a limited knowledge of noncoding regulatory elements complicate prioritization. Furthermore, large sample sizes are typically required for adequate power to identify the initial association signals. One important question is whether similar sample sizes need to be sequenced to identify the FSVs. Here, we present a proof-of-principle example of an extreme discordant design to map FSVs within the 2q33 low-risk breast cancer locus. Our approach employed DNA sequencing of a small number of discordant haplotypes to efficiently identify candidate FSVs. Our results were consistent with those from a 2,000-fold larger, traditional imputation-based fine-mapping study. To prioritize further, we used expression-quantitative trait locus analysis of RNA sequencing from breast tissues, gene regulation annotations from the ENCODE consortium, and functional assays for differential enhancer activities. Notably, we implicate three regulatory variants at 2q33 that target CASP8 (rs3769823, rs3769821 in CASP8, and rs10197246 in ALS2CR12) as functionally relevant. We conclude that nested discordant haplotype sequencing is a promising approach to aid mapping of low-risk association loci. The ability to include more efficient sequencing designs into mapping efforts presents an opportunity for the field to capitalize on the potential of association loci and accelerate translation of association signals to their underlying FSVs. Cancer Res; 76(7); 1916-25. ©2016 AACR.


Assuntos
Neoplasias da Mama/genética , Variação Genética/genética , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único , Risco
17.
Cell Physiol Biochem ; 37(5): 1671-85, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26536102

RESUMO

BACKGROUND/AIMS: Early parity reduces breast cancer risk, whereas, late parity and nulliparity increase breast cancer risk. Despite substantial efforts to understand the protective effects of early parity, the precise molecular circuitry responsible for these changes is not yet fully defined. METHODS: Here, we have conducted the first study assessing protein expression profiles in normal breast tissue of healthy early parous, late parous, and nulliparous women. Breast tissue biopsies were obtained from 132 healthy parous and nulliparous volunteers. These samples were subjected to global protein expression profiling and immunohistochemistry. GeneSpring and MetaCore bioinformatics analysis software were used to identify protein expression profiles associated with early parity (low risk) versus late/nulliparity (high risk). RESULTS: Early parity reduces expression of key proteins involved in mitogenic signaling pathways in breast tissue through down regulation of EGFR1/3, ESR1, AKT1, ATF, Fos, and SRC. Early parity is also characterized by greater genomic stability and reduced tissue inflammation based on differential expression of aurora kinases, p53, RAD52, BRCA1, MAPKAPK-2, ATF-1, ICAM1, and NF-kappaB compared to late and nulli parity. CONCLUSIONS: Early parity reduces basal cell proliferation in breast tissue, which translates to enhanced genomic stability, reduced cellular stress/inflammation, and thus reduced breast cancer risk.


Assuntos
Mama/metabolismo , Proteoma/análise , Transcriptoma , Adulto , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/prevenção & controle , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/genética , Proliferação de Células/genética , Biologia Computacional , Regulação para Baixo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Transdução de Sinais/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
18.
BMC Cancer ; 14: 644, 2014 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-25176219

RESUMO

BACKGROUND: microRNAs have recently succeeded in grabbing the center stage in cancer research for their potential to regulate vital cellular process like cell cycle, stem cell renewal and epithelial mesenchymal transition. Breast cancer is the second most leading cause of cancer related mortality in women. The main reason for mortality is chemoresistance and metastasis for which remnant stem cells are believed to be the cause. One of the natural ways to reduce the risk of breast cancer in women is early pregnancy. Unraveling the mechanism behind it would add to our knowledge and help in evolving newer paradigms for breast cancer prevention.The current study deals with investigating transcriptomic differences in putative stem cells in mammary epithelial cell population (MECs) in terms of genes and microRNAs. In silico tools were used to identify potential mechanisms. ALDH positive MECs represent a putative stem cell population in the mammary gland. METHODS: MECs were extracted from the mammary gland of virgin and parous (one time pregnant) rats. ALDH positive MECs were sorted and used for transcriptional and translational analysis for genes and microRNAs. In silico analysis for target prediction and networking was performed through online portals of Target Scan and Metacore. RESULTS: A total of 35 and 49 genes and microRNAs respectively were found to be differentially expressed within the two groups. Among the important genes were Lifr, Acvr1c, and Pparγ which were found to be targeted by microRNAs in our dataset like miR-143, miR-30, miR-140, miR-27b, miR-125a, miR-128ab, miR-342, miR-26ab, miR-181, miR-150, miR-23ab and miR-425. In silico data mining and networking also demonstrates that genes and microRNA interaction can have profound effects on stem cell renewal, cell cycle dynamics and EMT processes of the MEC population. CONCLUSIONS: Our data clearly shows that certain microRNAs play crucial role in the regulation of ALDH positive MECs and favor an anti-carcinogenic environment in the post-partum gland. Some of the potential interplaying mechanisms in the ALDH positive MEC population identified through this study are p21, Lifr and Pparγ mediated cell cycle regulation, regulation of metastasis and expansion of stem cell pool respectively.


Assuntos
Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Aldeído Oxirredutases/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Gravidez , Ratos , Ratos Endogâmicos Lew , Células-Tronco/metabolismo
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