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1.
Int J Cancer ; 140(1): 234-246, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27615392

RESUMO

The identification and validation of a targeted therapy for patients with triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. One of the key reasons for the failure to develop a new therapy for this subgroup of breast cancer patients has been the difficulty in identifying a highly prevalent, targetable molecular alteration in these tumors. Recently however, the p53 gene was found to be mutated in approximately 80% of basal/TNBC, raising the possibility that targeting the mutant p53 protein product might be a new approach for the treatment of this form of breast cancer. In this study, we investigated the anti-cancer activity of PRIMA-1 and PRIMA-1MET (APR-246), two compounds which were previously reported to reactivate mutant p53 and convert it to a form with wild-type (WT) properties. Using a panel of 18 breast cancer cell lines and 2 immortalized breast cell lines, inhibition of proliferation by PRIMA-1 and PRIMA-1MET was found to be cell-line dependent, but independent of cell line molecular subtype. Although response was independent of molecular subtype, p53 mutated cell lines were significantly more sensitive to PRIMA-1MET than p53 WT cells (p = 0.029). Furthermore, response (measured as IC50 value) correlated significantly with p53 protein level as measured by ELISA (p = 0.0089, r=-0.57, n = 19). In addition to inhibiting cell proliferation, PRIMA-1MET induced apoptosis and inhibited migration in a p53 mutant-dependent manner. Based on our data, we conclude that targeting mutant p53 with PRIMA-1MET is a potential new approach for treating p53-mutated breast cancer, including the subgroup with triple-negative (TN) disease.


Assuntos
Compostos Aza/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Mutação , Quinuclidinas/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Proteína Supressora de Tumor p53/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Mutação/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Proteína Supressora de Tumor p53/metabolismo
2.
Br J Cancer ; 112(12): 1895-903, 2015 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-26010411

RESUMO

BACKGROUND: Identification and validation of a targeted therapy for triple-negative breast cancer (TNBC), that is, breast cancers negative for oestrogen receptors, progesterone receptors and HER2 amplification, is currently one of the most urgent problems in breast cancer treatment. EGFR is one of the best-validated driver genes for TNBC. EGFR is normally activated following the release of ligands such as TGFα, mediated by the two MMP-like proteases ADAM (a disintegrin and metalloproteinase)-10 and ADAM-17. The aim of this study was to investigate the antitumour effects of a monoclonal antibody against ADAM-17 on an in vitro model of TNBC. METHODS: We investigated an inhibitory cross-domain humanised monoclonal antibody targeting both the catalytic domain and the cysteine-rich domain of ADAM17-D1(A12) in the HCC1937 and HCC1143 cell lines. RESULTS: D1(A12) was found to significantly inhibit the release of TGFα, and to decrease downstream EGFR-dependent cell signalling. D1(A12) treatment reduced proliferation in two-dimensional clonogenic assays, as well as growth in three-dimensional culture. Furthermore, D1(A12) reduced invasion of HCC1937 cells and decreased migration of HCC1143 cells. Finally, D1(A12) enhanced cell death in HCC1143 cells. CONCLUSION: Our in vitro findings suggest that targeting ADAM-17 with D1(A12) may have anticancer activity in TNBC cells.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteínas ADAM/imunologia , Proteína ADAM17 , Anticorpos Monoclonais Humanizados/imunologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Humanos , Terapia de Alvo Molecular , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
3.
Ann Oncol ; 24(2): 362-369, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22967992

RESUMO

BACKGROUND: Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 [i.e., those with triple-negative (TN) disease]. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR/HER family of receptors. PATIENTS AND METHODS: Expression of ADAM-17 was measured in 86 triple-negative and 96 non-triple-negative breast cancers. The ADAM-17 specific inhibitor, PF-5480090 (TMI-002, Pfizer) was tested in a panel of breast cancer cell lines for effects on functional outputs. RESULTS: In this study we show using both Western blotting and immunohistochemistry that ADAM-17 is expressed at significantly higher levels in TN than non-TN breast cancers. Using a panel of breast cancer cell lines in culture, PF-5480090 was found to decrease release of the EGFR ligand, TGF-alpha, decrease levels of phosphorylated EGFR and block cell proliferation in a cell-type-dependent manner. Potentially important was the finding of a significant and moderately strong correlation between ADAM-17 activity and extent of proliferation inhibition by PF-5480090 (r = 0.809; p = 0.003; n = 11). Pretreatment of cell lines with PF-5480090 enhanced response to several different cytotoxic and anti-EGFR/HER agents. CONCLUSION: It is concluded that inhibition of ADAM-17, especially in combination with chemotherapy or anti-EGFR/HER inhibitors, may be a new approach for treating breast cancer, including patients with TN disease.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptores ErbB/metabolismo , Proteínas ADAM/biossíntese , Proteína ADAM17 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Terapia de Alvo Molecular , Fosforilação/efeitos dos fármacos , RNA Mensageiro/biossíntese , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador alfa/metabolismo
4.
Ann Oncol ; 23(7): 1788-95, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22056974

RESUMO

BACKGROUND: Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by CD56+natural killer (NK) cells may contribute to the activity of trastuzumab in HER-2-amplified tumours. In this study, we investigated the possibility that trastuzumab might induce ADCC against HER-2-non-amplified breast cancer cells. METHODS: Induction of NK cell-mediated ADCC was examined in trastuzumab-treated HER-2-non-amplified breast cancer cell lines. HER-2 protein levels were also determined in tumour and autologous normal tissue samples from patients with HER-2 negative breast cancer. RESULTS: Trastuzumab induced a significant ADCC response in the HER-2-amplified HCC1954 and SKBR3 cell lines, and in all five of the non-amplified cell lines, which had low levels of detectable HER-2 by western blot (CAL-51, CAMA-1, MCF-7, T47D, and EFM19). Trastuzumab did not induce ADCC in the K562 control cell line or MDA-MB-468, which has very low levels of HER-2 detectable by enzyme-linked immunosorbent assay (ELISA) only. HER-2 protein was detected by ELISA in 14/15 patient tumour samples classified as HER-2-non-amplified. Significantly lower levels of HER-2 were detected in normal autologous tissue compared with tumour samples from the same patients. CONCLUSION: Our results suggest that HER-2-non-amplified breast cancer cells, with low but detectable levels of HER-2 protein, can bind trastuzumab and initiate ADCC.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos/farmacologia , Amplificação de Genes , Receptor ErbB-2/genética , Adulto , Anticorpos Monoclonais Humanizados/metabolismo , Antineoplásicos/metabolismo , Neoplasias da Mama , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Trastuzumab
5.
Ann Oncol ; 19(9): 1566-72, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18503039

RESUMO

Traditionally, matrix metalloproteinases (MMPs) have been implicated in cancer invasion and metastasis. Because of their role in these processes, several MMPs have been investigated for potential prognostic value as well as targets for antimetastatic therapy. In this investigation, we used a publically available database to relate messenger RNA expression levels for 17 different MMPs to tumor characteristics and outcome in patients with breast cancer. Of the MMPs investigated, only MMP-1 was significantly increased in tumors >2 cm in size compared with those

Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/mortalidade , Metaloproteinases da Matriz/metabolismo , Invasividade Neoplásica/patologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Quimioterapia Adjuvante , Estudos de Coortes , Terapia Combinada , Intervalos de Confiança , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Mastectomia Segmentar , Metaloproteinases da Matriz/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Probabilidade , Modelos de Riscos Proporcionais , RNA Mensageiro/análise , Radioterapia Adjuvante , Sistema de Registros , Medição de Risco , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Análise de Sobrevida , Resultado do Tratamento
6.
Ann Oncol ; 19(6): 1075-81, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18238782

RESUMO

ADAM-17 is a matrix metalloproteinase-like enzyme involved in the release of several ligands that have been shown to promote both cancer formation and progression. These ligands include transforming growth factor-alpha, amphiregulin, heparin-binding epidermal growth factor, epiregulin and tumor necrosis factor-alpha. In this investigation, we measured the expression of total ADAM-17 by enzyme-linked immunosorbent assay in 153 invasive breast cancers. We also measured the precursor and active forms by western blotting in 140 invasive breast cancers. Expression of ADAM-17 was significantly increased in high-grade compared with low-grade tumors and was independent of tumor size, lymph node metastasis and estrogen receptor status. Patients with high expression of ADAM-17 had a significantly shorter overall survival compared with those with low expression. Significantly, the prognostic impact of ADAM-17 was independent of conventional prognostic factors for breast cancer. Our results are further evidence that ADAM-17 is involved in breast cancer progression and thus provides further impetus for exploiting ADAM-17 as new target for cancer treatment.


Assuntos
Proteínas ADAM/biossíntese , Neoplasias da Mama/enzimologia , Proteína ADAM17 , Neoplasias da Mama/mortalidade , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico
7.
J Pathol ; 214(3): 283-93, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18095256

RESUMO

The formation of distant metastasis is the main cause of morbidity and mortality in patients with cancer. The aim of this article is to review recent advances in molecular and clinical aspects of metastasis. Traditionally, genes encoding extracellular matrix (ECM) processing proteases, adhesion proteins, and motility factors were thought to be amongst the main mediators of metastasis. Recently, however, genes activated during the early stages of tumourigenesis were implicated in the process. Conversely, genes thought to be primarily involved in metastasis such as urokinase plasminogen (uPA) and certain matrix metalloproteases (MMPs) are now known to also play a role in the early steps of tumour progression, perhaps by stimulating cell proliferation and/or promoting angiogenesis. Paradoxically, certain endogenous protease inhibitors such as PAI-1 and TIMP-1 appear to promote cancer metastasis rather than inhibiting the process. These recent advances in our understanding should lead to the development of new molecular markers for predicting the likely formation of metastasis as well as the identification of new targets for anti-metastatic therapies.


Assuntos
Regulação Neoplásica da Expressão Gênica , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Proteínas da Matriz Extracelular/genética , Marcadores Genéticos , Humanos , Metaloproteinases da Matriz/genética , Inibidores de Serina Proteinase/genética
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