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1.
Nat Commun ; 11(1): 2135, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358509

RESUMO

A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of Polybromo-1 (PBRM1) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that PBRM1/Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNγ target genes. An analysis of 3 independent patient cohorts and of murine pre-clinical models reveals that PBRM1 loss is associated with a less immunogenic TME and upregulated angiogenesis. Pbrm1 deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that PBRM1 mutation reduces benefit from ICB. Our study sheds light on the influence of PBRM1 mutations on IFNγ-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/microbiologia , Fatores de Transcrição/metabolismo , Animais , Complexo Antígeno-Anticorpo/genética , Complexo Antígeno-Anticorpo/metabolismo , Carcinoma de Células Renais/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Feminino , Imunofluorescência , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Neoplasias Renais/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mutação , Fosforilação , Fator de Transcrição STAT1/metabolismo , Análise Serial de Tecidos , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Transcriptoma/genética
2.
Cancer Cell ; 37(5): 720-734.e13, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32359397

RESUMO

Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. Replication stress conferred a therapeutic vulnerability to drugs targeting DNA-damage repair pathways. Elucidation of these previously unknown RMC hallmarks paves the way to new clinical trials for this rare but highly lethal malignancy.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Medular/patologia , Carcinoma de Células Renais/patologia , Aberrações Cromossômicas , Replicação do DNA , Neoplasias Renais/patologia , Proteína SMARCB1/metabolismo , Adulto , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Medular/genética , Carcinoma Medular/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Proliferação de Células , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína SMARCB1/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
5.
Clin Cancer Res ; 25(13): 3759-3771, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30760478

RESUMO

A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. Although PARP inhibitors as a class display many similarities, critical differences in structure can translate into differences in tolerability and antitumor activity that have important implications for the clinic. Furthermore, while PARP inhibitors have demonstrated a clear role in treating tumors with underlying homologous recombination deficiencies, there is now biological and early clinical evidence to support their use in other molecular subsets of cancer, including tumors associated with high levels of replication stress such as small-cell lung cancer. In this article, we highlight the key similarities and differences between individual PARP inhibitors and their implications for the clinic. We discuss data that currently support clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers, toward broader populations of patients through the use of novel biomarkers of homologous recombination repair deficiency (HRD), as well as predictive biomarkers rooted in mechanisms of sensitivity outside of HRD. We also explore the potential application of PARP inhibitors in earlier treatment settings, including neoadjuvant, adjuvant, and even chemoprevention approaches. Finally, we focus on promising combination therapeutic strategies, such as those with other DNA damage response (DDR) inhibitors such as ATR inhibitors, immune checkpoint inhibitors, and non-DDR-targeted agents that induce "chemical BRCAness."


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Proteína BRCA1/genética , Proteína BRCA2/genética , Estudos Clínicos como Assunto , Gerenciamento Clínico , Suscetibilidade a Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/mortalidade , Neoplasias/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , Resultado do Tratamento
6.
Nat Rev Clin Oncol ; 16(2): 81-104, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30356138

RESUMO

Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumour agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. In this Review, we discuss the current status of anticancer therapies targeting the DDR.


Assuntos
Antineoplásicos/uso terapêutico , Reparo do DNA/efeitos dos fármacos , Mutação , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Neoplasias/genética , Medicina de Precisão , Resultado do Tratamento
7.
Cancer Res ; 78(24): 6717-6725, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30498083

RESUMO

PARP inhibitors drive increased DNA damage, particularly in tumors with existing defects in DNA repair. This damage not only promotes immune priming through a range of molecular mechanisms, but also leads to adaptive upregulation of programmed death ligand 1 (PD-L1) expression. In this context, PARP inhibition and programmed cell death 1(PD-1)/PD-L1-targeting antibodies represent a rationale combination. In this review, we detail the basic and translational science underpinning this promising new combination, summarize available clinical data, and discuss the key questions that remain to be addressed during future development.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Anticorpos/química , Antígeno CTLA-4/metabolismo , Morte Celular , Dano ao DNA , Progressão da Doença , Humanos , Sistema Imunitário , Imunoterapia , Inflamação , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Pesquisa Médica Translacional
8.
Lancet Oncol ; 19(10): 1351-1359, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30236511

RESUMO

BACKGROUND: No approved systemic therapy exists for von Hippel-Lindau disease, an autosomal dominant disorder with pleiotropic organ manifestations that include clear cell renal cell carcinomas; retinal, cerebellar, and spinal haemangioblastomas; pheochromocytomas; pancreatic serous cystadenomas; and pancreatic neuroendocrine tumours. We aimed to assess the activity and safety of pazopanib in patients with von Hippel-Lindau disease. METHODS: In this non-randomised, single-centre, open-label, phase 2 trial, adult patients with clinical manifestations of von Hippel-Lindau disease were recruited from the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and were treated with pazopanib (800 mg orally daily) for 24 weeks, with an option to continue treatment if desired by the patient and treating physician. Primary endpoints were the proportion of patients who achieved an objective response and safety in the per-protocol population. The objective response was measured for each patient and each lesion type. Radiographic assessments were done at baseline and every 12 weeks throughout the study. Activity and safety were assessed with continuous monitoring and a Bayesian design. This study is registered with ClinicalTrials.gov, number NCT01436227, and is closed to accrual. FINDINGS: Between Jan 18, 2012, and Aug 10, 2016, we screened 37 patients with genetically confirmed or clinical features consistent with von Hippel-Lindau disease, of whom 31 eligible patients were treated with pazopanib. The proportion of patients who achieved an objective response was 42% (13 of 31 patients). By lesion sites responses were observed in 31 (52%) of 59 renal cell carcinomas, nine (53%) of 17 pancreatic lesions, and two (4%) of 49 CNS haemangioblastomas. Seven (23%) of 31 patients chose to stay on the treatment after 24 weeks. Four (13%) of 31 patients withdrew from the study because of grade 3 or 4 transaminitis, and three (10%) discontinued study treatment because of treatment intolerance with multiple intercurrent grade 1-2 toxicities. Treatment-related serious adverse events included one case each of appendicitis and gastritis and one patient had a fatal CNS bleed. INTERPRETATION: Pazopanib was associated with encouraging preliminary activity in von Hippel-Lindau disease, with a side-effect profile consistent with that seen in previous trials. Pazopanib could be considered as a treatment choice for patients with von Hippel-Lindau disease and growing lesions, or to reduce the size of unresectable lesions in these patients. The safety and activity of pazopanib in this setting warrants further investigation. FUNDING: Novartis Inc and NIH National Cancer Institute core grant.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Doença de von Hippel-Lindau/tratamento farmacológico , Adulto , Inibidores da Angiogênese/efeitos adversos , Feminino , Humanos , Masculino , Estudos Prospectivos , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Texas , Fatores de Tempo , Resultado do Tratamento , Doença de von Hippel-Lindau/diagnóstico por imagem , Doença de von Hippel-Lindau/genética
11.
Cancer ; 123(20): 3925-3932, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28657667

RESUMO

BACKGROUND: Prostate cancer has a significant heritable component, and rare deleterious germline variants in certain genes can increase the risk of the disease. The aim of the current study was to describe the prevalence of pathogenic germline variants in cancer-predisposing genes in men with prostate cancer and at least 1 additional primary cancer. METHODS: Using a multigene panel, the authors sequenced germline DNA from 102 men with prostate cancer and at least 1 additional primary cancer who also met ≥1 of the following criteria: 1) age ≤55 years at the time of diagnosis of the first malignancy; 2) rare tumor type or atypical presentation of a common tumor; and/or 3) ≥3 primary malignancies. Cancer family history and clinicopathologic data were independently reviewed by a clinical genetic counselor to determine whether the patient met established criteria for testing for a hereditary cancer syndrome. RESULTS: Sequencing identified approximately 3500 variants. Nine protein-truncating deleterious mutations were found across 6 genes, including BRCA2, ataxia telangiectasia mutated (ATM), mutL homolog 1 (MLH1), BRCA1 interacting protein C-terminal helicase 1 (BRIP1), partner and localizer of BRCA2 (PALB2), and fibroblast growth factor receptor 3 (FGFR3). Likely pathogenic missense variants were identified in checkpoint kinase 2 (CHEK2) and homeobox protein Hox-B13 (HOXB13). In total, 11 of 102 patients (10.8%) were found to have pathogenic or likely pathogenic mutations in cancer-predisposing genes. The majority of these men (64%) did not meet current clinical criteria for germline testing. CONCLUSIONS: Men with prostate cancer and at least 1 additional primary cancer are enriched for harboring a germline deleterious mutation in a cancer-predisposing gene that may impact cancer prognosis and treatment, but the majority do not meet current criteria for clinical genetic testing. Cancer 2017;123:3925-32. © 2017 American Cancer Society.


Assuntos
Mutação em Linhagem Germinativa , Segunda Neoplasia Primária/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias da Próstata/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA2/genética , Quinase do Ponto de Checagem 2/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi , Proteínas de Grupos de Complementação da Anemia de Fanconi , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Mutação de Sentido Incorreto , Síndromes Neoplásicas Hereditárias/diagnóstico , Proteínas Nucleares/genética , RNA Helicases/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Análise de Sequência de DNA , Proteínas Supressoras de Tumor/genética
12.
Kidney Cancer ; 1(1): 57-64, 2017 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-30334005

RESUMO

Background: Approximately 16% of patients with renal cell carcinomas (RCC) present with stage IV disease at time of diagnosis. Treatment options for metastatic clear cell RCC, the most common histologic subtype, have proliferated over the past decade and include a combination of surgery and systemic therapy. The selection of systemic agent and best timing of systemic therapy in relation to nephrectomy is an area of active research. Objective: To evaluate the evidence for perioperative systemic therapy, including presurgical and postsurgical, for metastatic RCC. Methods: A systematic literature search using PubMed and MEDLINE databases was performed in January 2017 for articles related to perioperative systemic therapy in metastatic RCC using key word search terms. The authors screened the search results and identified selected publications by predetermined inclusion criteria and consensus. Expert opinion was obtained to assess for publications missed by search. Results: Early phase clinical trials of antiangiogenic tyrosine kinase inhibitors prior to cytoreductive nephrectomy in select patients show that these systemic agents are safe and effective in the presurgical setting. There are no randomized data evaluating pre- or post-surgical systemic therapy in metastatic RCC. Conclusions: Retrospective and early-phase prospective studies on the use and timing of systemic therapy in relation to cytoreductive nephrectomy in metastatic RCC show that standard of care antiangiogenic agents are safe and effective in the perioperative setting, though randomized data are still lacking. Pre-surgical immune checkpoint therapy for metastatic RCC has strong biologic rationale and holds promise. Sequential tumor sampling in neoadjuvant and presurgical trials is necessary to determine biomarkers of response and resistance.

15.
Breast Cancer Res Treat ; 132(2): 487-98, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21647677

RESUMO

Normal mammary gland homeostasis requires the coordinated regulation of protein signaling networks. However, we have little prospective information on whether activation of protein signaling occurs in premalignant mammary epithelial cells, as represented by cells with cytological atypia from women who are at high risk for breast cancer. This information is critical for understanding the role of deregulated signaling pathways in the initiation of breast cancer and for developing targeted prevention and/or treatment strategies for breast cancer in the future. In this pilot and feasibility study, we examined the expression of 52 phosphorylated, total, and cleaved proteins in 31 microdissected Random Periareolar Fine Needle Aspiration (RPFNA) samples by high-throughput Reverse Phase Protein Microarray. Unsupervised hierarchical clustering analysis indicated the presence of four clusters of proteins that represent the following signaling pathways: (1) receptor tyrosine kinase/Akt/mammalian target of rapamycin (RTK/Akt/mTOR), (2) RTK/Akt/extracellular signal-regulated kinase (RTK/Akt/ERK), (3) mitochondrial apoptosis, and (4) indeterminate. Clusters 1 through 3 comprised moderately to highly expressed proteins, while Cluster 4 comprised proteins that are lowly expressed in a majority of RPFNA samples. Our exploratory study showed that the interlinked components of mitochondrial apoptosis pathway are highly expressed in all mammary epithelial cells obtained from high-risk women. In particular, the expression levels of anti-apoptotic Bcl-xL and pro-apoptotic Bad are positively correlated in both non-atypical and atypical samples (unadjusted P < 0.0001), suggesting a delicate balance between the pro-apoptotic and anti-apoptotic regulation of cell proliferation during the early steps of mammary carcinogenesis. Our feasibility study suggests that the activation of key proteins along the RTK/Akt pathway may tip this balance to cell survival. Taken together, our results demonstrate the feasibility of mapping proteomic signaling networks in limited RPFNA samples obtained from high-risk women and the promise of developing rational drug targets or preventative strategies for breast cancer in future proteomic studies with a larger cohort of high-risk women.


Assuntos
Proteínas Reguladoras de Apoptose/análise , Neoplasias da Mama/química , Proteínas de Ciclo Celular/análise , Glândulas Mamárias Humanas/química , Proteômica , Transdução de Sinais , Adulto , Idoso , Apoptose , Biópsia por Agulha Fina , Neoplasias da Mama/patologia , Sobrevivência Celular , Análise por Conglomerados , Estudos de Viabilidade , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Modelos Logísticos , Glândulas Mamárias Humanas/patologia , Microdissecção , Pessoa de Meia-Idade , North Carolina , Projetos Piloto , Estudos Prospectivos , Análise Serial de Proteínas , Proteômica/métodos , Medição de Risco , Fatores de Risco
16.
Cancer Epidemiol Biomarkers Prev ; 20(3): 476-82, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21242333

RESUMO

BACKGROUND: Obesity is a well-established risk factor for cancer, accounting for up to 20% of cancer deaths in women. Studies of women with breast cancer have shown obesity to be associated with an increased risk of dying from breast cancer and increased risk of developing distant metastasis. While previous studies have focused on differences in circulating hormone levels as a cause for increased breast cancer incidence in postmenopausal women, few studies have focused on potential differences in the protein expression patterns of mammary epithelial cells obtained from obese versus nonobese women. METHODS: Protein expression was assessed by reverse-phase protein microarray in mammary epithelial cells from 31 random periareolar fine needle aspirations performed on 26 high-risk women. RESULTS: In this pilot and exploratory study, vimentin (unadjusted P=0.028) expression was significantly different between obese and nonobese women. CONCLUSIONS: Vimentin is integral both to adipocyte structure and function and to the epithelial-to-mesenchymal transition needed for cancer cell metastasis. Further research is needed to confirm this finding and determine the possible effects of the adipocyte microenvironment on the initiation and progression of breast cancer in high-risk women. IMPACT: Differential protein expression patterns obtained from a future expanded study may serve to elaborate the underlying pathology of breast cancer initiation and progression in obese women and identify potential biomarkers of response to preventative interventions such as dietary changes and exercise.


Assuntos
Neoplasias da Mama/metabolismo , Glândulas Mamárias Humanas/metabolismo , Obesidade/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Biópsia por Agulha Fina/métodos , Índice de Massa Corporal , Neoplasias da Mama/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Imuno-Histoquímica , Glândulas Mamárias Humanas/patologia , Pessoa de Meia-Idade , Obesidade/patologia , Projetos Piloto , Análise Serial de Proteínas/métodos , Estudos Retrospectivos , Fatores de Risco , Vimentina/metabolismo
17.
Cancer Epidemiol Biomarkers Prev ; 18(3): 901-14, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19258476

RESUMO

BACKGROUND: Only 5% of all breast cancers are the result of BRCA1/2 mutations. Methylation silencing of tumor suppressor genes is well described in sporadic breast cancer; however, its role in familial breast cancer is not known. METHODS: CpG island promoter methylation was tested in the initial random periareolar fine-needle aspiration sample from 109 asymptomatic women at high risk for breast cancer. Promoter methylation targets included RARB (M3 and M4), ESR1, INK4a/ARF, BRCA1, PRA, PRB, RASSF1A, HIN-1, and CRBP1. RESULTS: Although the overall frequency of CpG island promoter methylation events increased with age (P<0.0001), no specific methylation event was associated with age. In contrast, CpG island methylation of RARB M4 (P=0.051), INK4a/ARF (P=0.042), HIN-1 (P=0.044), and PRA (P=0.032), as well as the overall frequency of methylation events (P=0.004), was associated with abnormal Masood cytology. The association between promoter methylation and familial breast cancer was tested in 40 unaffected premenopausal women in our cohort who underwent BRCA1/2 mutation testing. Women with BRCA1/2 mutations had a low frequency of CpG island promoter methylation (15 of 15 women had

Assuntos
Neoplasias da Mama/genética , Ilhas de CpG/genética , Biópsia por Agulha Fina , Distribuição de Qui-Quadrado , Inibidor p16 de Quinase Dependente de Ciclina/genética , Citocinas/genética , Metilação de DNA , Feminino , Genes BRCA1 , Genes BRCA2 , Genes Supressores de Tumor , Humanos , Mutação , Reação em Cadeia da Polimerase , Pré-Menopausa , Regiões Promotoras Genéticas/genética , Receptores de Progesterona/genética , Receptores do Ácido Retinoico/genética , Risco , Medição de Risco , Estatísticas não Paramétricas , Proteínas Supressoras de Tumor/genética
18.
Cancer Epidemiol Biomarkers Prev ; 17(8): 1884-90, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18708376

RESUMO

PURPOSE: Currently, we lack biomarkers to predict whether high-risk women with mammary atypia will respond to tamoxifen chemoprevention. EXPERIMENTAL DESIGN: Thirty-four women with cytologic mammary atypia from the Duke University High-Risk clinic were offered tamoxifen chemoprevention. We tested whether ESR1 promoter hypermethylation and/or estrogen receptor (ER) protein expression by immunohistochemistry predicted persistent atypia in 18 women who were treated with tamoxifen for 12 months and in 16 untreated controls. RESULTS: We observed a statistically significant decrease in the Masood score of women on tamoxifen chemoprevention for 12 months compared with control women. This was a significant interaction effect of time (0, 6, and 12 months) and treatment group (tamoxifen versus control) P = 0.0007. However, neither ESR1 promoter hypermethylation nor low ER expression predicted persistent atypia in Random Periareolar Fine Needle Aspiration after 12 months tamoxifen prevention. CONCLUSIONS: Results from this single institution pilot study provide evidence that, unlike for invasive breast cancer, ESR1 promoter hypermethylation and/or low ER expression is not a reliable marker of tamoxifen-resistant atypia.


Assuntos
Antineoplásicos Hormonais/farmacologia , Biópsia por Agulha Fina/métodos , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Quimioprevenção , Metilação de DNA , Receptor alfa de Estrogênio/genética , Tamoxifeno/farmacologia , Adulto , Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Regiões Promotoras Genéticas , Tamoxifeno/administração & dosagem , Fatores de Tempo
19.
Clin Cancer Res ; 13(22 Pt 1): 6834-41, 2007 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18006786

RESUMO

PURPOSE: p16(INK4a) has been appreciated as a key regulator of cell cycle progression and senescence. Cultured human mammary epithelial cells that lack p16(INK4a) activity have been shown to exhibit premalignant phenotypes, such as telomeric dysfunction, centrosomal dysfunction, a sustained stress response, and, most recently, a dysregulation of chromatin remodeling and DNA methylation. These data suggest that cells that lack p16(INK4a) activity would be at high risk for breast cancer development and may exhibit an increased frequency of DNA methylation events in early cancer. EXPERIMENTAL DESIGN: To test this hypothesis, the frequencies of INK4a/ARF promoter hypermethylation, as well as four additional selected loci, were tested in the initial random periareolar fine needle aspiration samples from 86 asymptomatic women at high risk for development of breast cancer, stratified using the Masood cytology index. RESULTS: INK4a/ARF promoter hypermethylation was observed throughout all early stages of intraepithelial neoplasia and, importantly, in morphologically normal-appearing mammary epithelial cells; 29 of 86 subjects showed INK4a/ARF promoter hypermethylation in at least one breast. Importantly, INK4a/ARF promoter hypermethylation was not associated with atypia, and the frequency of hypermethylation did not increase with increasing Masood cytology score. The frequency of INK4a/ARF promoter hypermethylation was associated with the combined frequency of promoter hypermethylation of retinoic acid receptor-beta2, estrogen receptor-alpha, and breast cancer-associated 1 genes (P = 0.001). CONCLUSIONS: Because INK4a/ARF promoter hypermethylation does not increase with age but increases with the frequency of other methylation events, we predict that INK4a/ARF promoter hypermethylation may serve as a marker of global methylation dysregulation.


Assuntos
Neoplasias da Mama/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA , Inativação Gênica , Glândulas Mamárias Humanas/metabolismo , Adulto , Idoso , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Humanos , Glândulas Mamárias Humanas/citologia , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Risco
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