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1.
Breast Cancer Res Treat ; 148(1): 19-31, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25266129

RESUMO

Breast cancer (BC) is a disease with intra- and inter-tumor heterogeneity, and models representing the complete variety of clinical BC phenotypes are not available. We explored the tumor growth potential and metastatic behavior of human BC cell lines and determined whether these cell lines can recapitulate subtype-related biological characteristics of tumors. Eighteen human BC cell lines were implanted under the mammary fat pad of nude mice. Subtype-specific differences in tumor growth, metastatic ability to distant sites, and tumor-related survival of mice were recorded. Eighty-nine percent of the cell lines gave rise to xenografts of which 56 % showed metastasis to distant sites. A clear difference was observed in growth of xenografts from cell lines of different molecular subtypes (P = 0.001; Kruskal-Wallis test). Mice bearing the basal-like and the normal-like xenografts showed poor tumor-related survival (HR: 10.50; P = 0.002 and HR: 9.89; P = 0.003, respectively) compared with those bearing the ERBB2-positive xenografts, which had the longest survival. Subtype-specific metastasis to distant sites between xenografts was not however observed. Comparable to clinical behavior in humans, we observed that the basal-like and the normal-like cell lines grew more aggressively in mice than the cell lines of other molecular subtypes. However, in contrast to clinical findings, we observed no relationships between intrinsic subtype and preferences for site of relapse. Importantly, we have established xenograft models from 16 phenotypically and molecularly diverse human BC cell lines, which can be exploited as useful tools to perform functional studies and screening of interfering drugs.


Assuntos
Neoplasias da Mama/patologia , Linhagem Celular Tumoral/patologia , Modelos Animais de Doenças , Animais , Feminino , Humanos , Camundongos , Camundongos Nus , Invasividade Neoplásica/patologia , Transplante Heterólogo
2.
J Cell Physiol ; 226(7): 1741-9, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21506106

RESUMO

Resistance to the antiestrogen tamoxifen remains a major problem in the management of estrogen receptor-positive breast cancer. Knowledge on the resistance mechanisms is needed to develop more effective therapies. Breast cancer antiestrogen resistance 4 (BCAR4) was identified in a functional screen for genes involved in tamoxifen resistance. BCAR4 is expressed in 27% of primary breast tumors. In patients treated with tamoxifen for metastized disease high BCAR4 mRNA levels are associated with reduced clinical benefit and progression-free survival. Regarding tumor aggressiveness high BCAR4 mRNA levels are associated with a shorter metastasis free survival and overall survival. In the present study, we investigated the role of BCAR4 in endocrine resistance. Forced expression of BCAR4 in human ZR-75-1 and MCF7 breast cancer cells resulted in cell proliferation in the absence of estrogen and in the presence of various antiestrogens. Inhibition of estrogen receptor 1 (ESR1) expression with small interfering RNA (siRNA), implied that the BCAR4-induced mechanism of resistance is independent of ESR1. Highly conserved BCAR4 homologues of rhesus monkey, green monkey, and the less conserved common marmoset gene induced tamoxifen-resistant cell proliferation, in contrast to the distant BCAR4 homologues of bovine and rabbit. Injection of BCAR4-expressing ZR-75-1 cells into nude mice resulted in rapidly growing tumors. In silico analysis showed that BCAR4 mRNA is highly expressed in human placenta and oocyte, and absent in other normal tissues. In conclusion, BCAR4 is a strong transforming gene causing estrogen-independent growth and antiestrogen resistance, and induces tumor formation in vivo. Due to its restricted expression, BCAR4 may be a good target for treating antiestrogen-resistant breast cancer.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/metabolismo , Proteína Substrato Associada a Crk/metabolismo , Resistencia a Medicamentos Antineoplásicos , Moduladores de Receptor Estrogênico/farmacologia , Tamoxifeno/farmacologia , Sequência de Aminoácidos , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteína Substrato Associada a Crk/genética , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Haplorrinos , Humanos , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Oncogenes , Oócitos/metabolismo , Placenta/metabolismo , Gravidez , Interferência de RNA , RNA Longo não Codificante , RNA Mensageiro/metabolismo , RNA não Traduzido , Coelhos , Fatores de Tempo , Transfecção , Carga Tumoral
3.
Cancer Res ; 68(5): 1581-92, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18316624

RESUMO

Vascular endothelial growth factor receptors (VEGFR) have important roles in cancer, affecting blood and lymphatic vessel functionality as well as tumor cells themselves. We compared the efficacy of a VEGFR tyrosine kinase inhibitor, PTK787/ZK222584 (PTK/ZK), which targets the three VEGFRs, with blocking antibodies directed against VEGFR-2 (DC101) or VEGF-A (Pab85618) in a metastatic melanoma model. Although all inhibitors exerted comparable effects on primary tumor growth, only PTK/ZK significantly reduced lymph node metastasis formation. A comparable decrease in lymphatic vessel density following blockade of VEGFR-2 (DC101) or the three VEGFRs (PTK/ZK) was observed in the metastases. However, the functionality of lymphatics surrounding the primary tumor was more significantly disrupted by PTK/ZK, indicating the importance of multiple VEGFRs in the metastatic process. The antimetastatic properties of PTK/ZK were confirmed in a breast carcinoma model. B16/BL6 tumor cells express VEGF ligands and their receptors. Blockade of a VEGFR-1 autocrine loop with PTK/ZK inhibited tumor cell migration. Furthermore, the tumor cells also showed enhanced sensitivity to platinum-based chemotherapy in combination with PTK/ZK, indicating that autocrine VEGFRs are promoting tumor cell migration and survival. In summary, our results suggest that, in addition to blocking angiogenesis, combined inhibition of the three VEGFRs may more efficiently target other aspects of tumor pathophysiology, including lymphatic vessel functionality, tumor cell dissemination, survival pathways, and response to chemotherapeutic compounds.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Metástase Linfática , Melanoma Experimental , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Neovascularização Patológica , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
J Med Chem ; 50(26): 6638-46, 2007 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-18052026

RESUMO

A set of small nonpeptidic diaryl phosphonate inhibitors was prepared. Some of these inhibitors show potent and highly selective irreversible uPA inhibition. The biochemical and modeling data prove that the combination of a benzylguanidine moiety with a diaryl phosphonate ester results in optimized molecules for derivatizing the serine alcohol in the uPA active site. Selected compounds show significant antimetastatic effects in the BN-472 rat mammary carcinoma model. We report in this paper a preclinical proof of concept that selective, irreversible uPA inhibitors could be valuable in antimetastatic therapy.


Assuntos
Antineoplásicos/síntese química , Guanidinas/síntese química , Neoplasias Mamárias Animais/tratamento farmacológico , Organofosfonatos/síntese química , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Feminino , Guanidinas/química , Guanidinas/farmacologia , Neoplasias Mamárias Animais/patologia , Modelos Moleculares , Metástase Neoplásica , Organofosfonatos/química , Organofosfonatos/farmacologia , Ratos , Relação Estrutura-Atividade
5.
Thromb Haemost ; 93(4): 779-86, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15841327

RESUMO

The serine protease uPA (urokinase-type plasminogen activator) and its receptor uPAR (CD87) are often elevated in malignant tumours, hence, inhibition of this tumour-associated plasminogen activation system provides an attractive target for therapeutic strategies. WX-UK1, a derivative of 3-aminophenylalanine in the L-conformation with inhibitory antiproteolytic properties, was tested for its specificity spectrum using specific chromogenic paranitroanilide peptide substrates. The corresponding D-enantiomer of WX-UK1 was used as a control. The anti-tumour and anti-metastatic (number of lung foci and weight of the axillary lymph nodes) properties were studied by subcutaneous administration of WX-UK1 to Brown Norwegian (BN) rats carrying orthotopically transplanted BN472 rat breast tumours. WX-UK1 selectively inhibited tumour-related proteases from rats and humans such as uPA, plasmin, or thrombin in the sub or low micromolar range. The activity was stereoselective as the D-enantiomer of WX-UK1 inhibited uPA and plasmin at approximately 70-fold higher Ki values than the active L-form. Chronical administration of the L-enantiomer of WXUK1 impaired primary tumour growth and metastasis of BN472 rat breast cancer in a dose-dependent manner. The minimum inhibitory dosage with maximal effect was between 0.15 and 0.3 mg/kg/day. The inactive D-enatiomer of WX-UK1 was not active in this respect. Daily treatment with WX-UK1 for up to 35 days was well tolerated as judged by the unchanged body and organ weight development. In conclusion, our results provide evidence that WX-UK1 as a single agent inhibits breast tumour growth and metastasis in vivo, and thus is a promising candidate drug to treat human cancer.


Assuntos
Neoplasias Mamárias Animais/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Animais/patologia , Metástase Neoplásica/tratamento farmacológico , Transplante de Neoplasias , Fenilalanina/análogos & derivados , Fenilalanina/uso terapêutico , Inibidor 1 de Ativador de Plasminogênio/genética , RNA Neoplásico/análise , Ratos , Ratos Endogâmicos BN , Receptores de Superfície Celular/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase , Ativador de Plasminogênio Tipo Uroquinase/genética
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