Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
Cancer Cell ; 4(3): 223-38, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-14522256

RESUMEN

Increased Myc gene copy number is observed in human prostate cancer. To define Myc's functional role, we generated transgenic mice expressing human c-Myc in the mouse prostate. All mice developed murine prostatic intraepithelial neoplasia followed by invasive adenocarcinoma. Microarray-based expression profiling identified a Myc prostate cancer expression signature, which included the putative human tumor suppressor NXK3.1. Human prostate tumor databases revealed modules of human genes that varied in concert with the Myc prostate cancer signature. This module includes the Pim-1 kinase, a gene known to cooperate with Myc in tumorigenesis, and defines a subset of human, "Myc-like" human cancers. This approach illustrates how genomic technologies can be applied to mouse cancer models to guide evaluation of human tumor databases.


Asunto(s)
Adenocarcinoma/fisiopatología , Genes myc/fisiología , Próstata/fisiopatología , Neoplasias de la Próstata/fisiopatología , Andrógenos/metabolismo , Animales , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/fisiología , Genes myc/genética , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Ratones , Ratones Transgénicos , Neovascularización Patológica , Orquiectomía , Neoplasia Intraepitelial Prostática/fisiopatología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-pim-1 , Factores de Transcripción/metabolismo
2.
Prostate ; 70(6): 591-600, 2010 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-19938013

RESUMEN

BACKGROUND: Hepsin is a cell surface protease that is over-expressed in more than 90% of human prostate cancer cases. The previously developed Probasin-hepsin/Large Probasin-T antigen (PB-hepsin/LPB-Tag) bigenic mouse model of prostate cancer demonstrates that hepsin promotes primary tumors that are a mixture of adenocarcinoma and neuroendocrine (NE) lesions, and metastases that are NE in nature. However, since the majority of human prostate tumors are adenocarcinomas, the contribution of hepsin in the progression of adenocarcinoma requires further investigation. METHODS: We crossed the PB-hepsin mice with PB-Hi-myc transgenic mouse model of prostate adenocarcinoma and characterized the tumor progression in the resulting PB-hepsin/PB-Hi-myc bigenic mice. RESULTS: We report that PB-hepsin/PB-Hi-myc bigenic mice develop invasive adenocarcinoma at 4.5 months. Further, histological analysis of the 12- to 17-month-old mice revealed that the PB-hepsin/PB-Hi-myc model develops a higher grade adenocarcinoma compared with age-matched tumors expressing only PB-Hi-myc. Consistent with targeting hepsin to the prostate, the PB-hepsin/PB-Hi-myc tumors showed higher hepsin expression as compared to the age-matched myc tumors. Furthermore, endogenous expression of hepsin increased in the PB-Hi-myc mice as the tumors progressed. CONCLUSIONS: Although we did not detect any metastases from the prostates in either the PB-hepsin/PB-Hi-myc or the PB-Hi-myc mice, our data suggests that hepsin and myc cooperate during the progression to high-grade prostatic adenocarcinoma.


Asunto(s)
Adenocarcinoma/metabolismo , Progresión de la Enfermedad , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Serina Endopeptidasas/metabolismo , Adenocarcinoma/patología , Proteína de Unión a Andrógenos/genética , Proteína de Unión a Andrógenos/metabolismo , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Transgénicos , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-myc/genética , Serina Endopeptidasas/genética , Factores de Tiempo
4.
Cancer Res ; 66(21): 10513-6, 2006 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-17079473

RESUMEN

Persistent androgen receptor signaling has been implicated as a critical factor in prostate cancer progression even at the hormone-refractory stage and provides strong rationale for developing novel androgen receptor antagonists. Traditional models for in vivo evaluation of antiandrogens are cumbersome because they rely on physiologic end points, such as the size of androgen-dependent tissues. Here, we describe a transgenic mouse (ARR2 Pb-Lux) that expresses luciferase specifically in the prostate in an androgen-dependent fashion. This signal is reduced by castration or by treatment with bicalutamide and can be quantified through noninvasive bioluminescent imaging. ARR2 Pb-Lux mice provide a novel method for rapid pharmacodynamic evaluation of novel pharmacologic compounds designed to inhibit androgen receptor signaling.


Asunto(s)
Antagonistas de Andrógenos/farmacología , Anilidas/farmacología , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/fisiología , Animales , Femenino , Luciferasas/genética , Masculino , Ratones , Ratones Transgénicos , Nitrilos , Receptores Androgénicos/genética , Compuestos de Tosilo
5.
Cancer Res ; 65(24): 11565-71, 2005 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-16357166

RESUMEN

Insights into the molecular basis of hormone-refractory prostate cancer have principally relied on human prostate cancer cell lines, all of which were derived from patients who had already failed hormonal therapy. Recent progress in developing genetically engineered mouse prostate cancer models provides an opportunity to isolate novel cell lines from animals never exposed to hormone ablation, avoiding any potential bias conferred by the selective pressure of the castrate environment. Here we report the isolation of such a cell line (Myc-CaP) from a c-myc transgenic mouse with prostate cancer. Myc-CaP cells have an amplified androgen receptor gene despite no prior exposure to androgen withdrawal and they retain androgen-dependent transgene expression as well as androgen-dependent growth in soft agar and in mice. Reexpression of c-Myc from a hormone-independent promoter rescues growth in androgen-depleted agar but not in castrated mice, showing a clear distinction between the molecular requirements for hormone-refractory growth in vitro versus in vivo. Myc-CaP cells represent a unique reagent for dissecting discreet steps in hormone-refractory prostate cancer progression and show the general utility of using genetically engineered mouse models for establishing new prostate cancer cell lines.


Asunto(s)
Andrógenos/fisiología , Neoplasias Hormono-Dependientes , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-myc/fisiología , Receptores Androgénicos/metabolismo , Animales , Castración , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Ingeniería Genética , Humanos , Masculino , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Transgénicos , Neoplasias Hormono-Dependientes/genética , Neoplasias Hormono-Dependientes/metabolismo , Neoplasias Hormono-Dependientes/patología , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-myc/genética , Células Madre/citología , Células Madre/metabolismo , Células Tumorales Cultivadas
6.
PLoS One ; 6(3): e17449, 2011 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-21394210

RESUMEN

MYC and phosphoinositide 3-kinase (PI3K)-pathway deregulation are common in human prostate cancer. Through examination of 194 human prostate tumors, we observed statistically significant co-occurrence of MYC amplification and PI3K-pathway alteration, raising the possibility that these two lesions cooperate in prostate cancer progression. To investigate this, we generated bigenic mice in which both activated human AKT1 and human MYC are expressed in the prostate (MPAKT/Hi-MYC model). In contrast to mice expressing AKT1 alone (MPAKT model) or MYC alone (Hi-MYC model), the bigenic phenotype demonstrates accelerated progression of mouse prostate intraepithelial neoplasia (mPIN) to microinvasive disease with disruption of basement membrane, significant stromal remodeling and infiltration of macrophages, B- and T-lymphocytes, similar to inflammation observed in human prostate tumors. In contrast to the reversibility of mPIN lesions in young MPAKT mice after treatment with mTOR inhibitors, Hi-MYC and bigenic MPAKT/Hi-MYC mice were resistant. Additionally, older MPAKT mice showed reduced sensitivity to mTOR inhibition, suggesting that additional genetic events may dampen mTOR dependence. Since increased MYC expression is an early feature of many human prostate cancers, these data have implications for treatment of human prostate cancers with PI3K-pathway alterations using mTOR inhibitors.


Asunto(s)
Lesiones Precancerosas/enzimología , Neoplasias de la Próstata/enzimología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Activación Enzimática/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Transgénicos , Invasividad Neoplásica , Fenotipo , Lesiones Precancerosas/patología , Próstata/efectos de los fármacos , Próstata/patología , Neoplasia Intraepitelial Prostática/enzimología , Neoplasia Intraepitelial Prostática/patología , Neoplasias de la Próstata/patología , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo
7.
Cancer Res ; 71(8): 3052-65, 2011 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-21493594

RESUMEN

PDK1 activates AKT suggesting that PDK1 inhibition might suppress tumor development. However, while PDK1 has been investigated intensively as an oncology target, selective inhibitors suitable for in vivo studies have remained elusive. In this study we present the results of in vivo PDK1 inhibition through a universally applicable RNAi approach for functional drug target validation in oncogenic pathway contexts. This approach, which relies on doxycycline-inducible shRNA expression from the Rosa26 locus, is ideal for functional studies of genes like PDK1 where constitutive mouse models lead to strong developmental phenotypes or embryonic lethality. We achieved more than 90% PDK1 knockdown in vivo, a level sufficient to impact physiological functions resulting in hyperinsulinemia and hyperglycemia. This phenotype was reversible on PDK1 reexpression. Unexpectedly, long-term PDK1 knockdown revealed a lack of potent antitumor efficacy in 3 different mouse models of PTEN-deficient cancer. Thus, despite efficient PDK1 knockdown, inhibition of the PI3K pathway was marginal suggesting that PDK1 was not a rate limiting factor. Ex vivo analysis of pharmacological inhibitors revealed that AKT and mTOR inhibitors undergoing clinical development are more effective than PDK1 inhibitors at blocking activated PI3K pathway signaling. Taken together our findings weaken the widely held expectation that PDK1 represents an appealing oncology target.


Asunto(s)
Neoplasias Experimentales/enzimología , Fosfohidrolasa PTEN/deficiencia , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Leucemia Experimental/enzimología , Leucemia Experimental/genética , Masculino , Ratones , Ratones Transgénicos , Neoplasias Experimentales/genética , Proteína Oncogénica v-akt/antagonistas & inhibidores , Proteína Oncogénica v-akt/metabolismo , Fosfohidrolasa PTEN/genética , Fosforilación , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/genética , Proteínas Serina-Treonina Quinasas/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Interferencia de ARN
8.
Cancer Res ; 68(16): 6762-9, 2008 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-18701501

RESUMEN

Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regression of the disease. However, the tumor will progress to an "androgen-independent" stage that results in renewed growth and spread of the cancer. Both nuclear factor-kappaB (NF-kappaB) expression and neuroendocrine differentiation predict poor prognosis, but their precise contribution to prostate cancer progression is unknown. This report shows that secretory proteins from neuroendocrine cells will activate the NF-kappaB pathway in LNCaP cells, resulting in increased levels of active androgen receptor (AR). By blocking NF-kappaB signaling in vitro, AR activation is inhibited. In addition, the continuous activation of NF-kappaB signaling in vivo by the absence of the IkappaBalpha inhibitor prevents regression of the prostate after castration by sustaining high levels of nuclear AR and maintaining differentiated function and continued proliferation of the epithelium. Furthermore, the NF-kappaB pathway was activated in the ARR(2)PB-myc-PAI (Hi-myc) mouse prostate by cross-breeding into a IkappaBalpha(+/-) haploid insufficient line. After castration, the mouse prostate cancer continued to proliferate. These results indicate that activation of NF-kappaB is sufficient to maintain androgen-independent growth of prostate and prostate cancer by regulating AR action. Thus, the NF-kappaB pathway may be a potential target for therapy against androgen-independent prostate cancer.


Asunto(s)
Carcinoma Neuroendocrino/patología , Regulación Neoplásica de la Expresión Génica , FN-kappa B/metabolismo , Neoplasias Hormono-Dependientes/patología , Neoplasias de la Próstata/patología , Receptores Androgénicos/metabolismo , Andrógenos/farmacología , Animales , Apoptosis , Western Blotting , Castración , Núcleo Celular/metabolismo , Progresión de la Enfermedad , Humanos , Quinasa I-kappa B/fisiología , Masculino , Ratones , Ratones Noqueados , FN-kappa B/genética , Neoplasias Hormono-Dependientes/genética , Neoplasias Hormono-Dependientes/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Androgénicos/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Transcripción Genética , Células Tumorales Cultivadas
9.
Cancer Cell ; 14(2): 146-55, 2008 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-18691549

RESUMEN

Transgenic expression of activated AKT1 in the murine prostate induces prostatic intraepithelial neoplasia (PIN) that does not progress to invasive prostate cancer (CaP). In luminal epithelial cells of Akt-driven PIN, we show the concomitant induction of p27(Kip1) and senescence. Genetic ablation of p27(Kip1) led to downregulation of senescence markers and progression to cancer. In humans, p27(Kip1) and senescence markers were elevated in PIN not associated with CaP but were decreased or absent, respectively, in cancer-associated PIN and in CaP. Importantly, p27(Kip1) upregulation in mouse and human in situ lesions did not depend upon mTOR or Akt activation but was instead specifically associated with alterations in cell polarity, architecture, and adhesion molecules. These data suggest that a p27(Kip1)-driven checkpoint limits progression of PIN to CaP.


Asunto(s)
Senescencia Celular , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Neoplasia Intraepitelial Prostática/metabolismo , Neoplasia Intraepitelial Prostática/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Alelos , Animales , Animales Modificados Genéticamente , Biomarcadores/metabolismo , Adhesión Celular , Comunicación Celular , Línea Celular , Polaridad Celular , Proliferación Celular , Progresión de la Enfermedad , Células Epiteliales/patología , Humanos , Masculino , Ratones , Mutación/genética , Fenotipo , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Serina-Treonina Quinasas TOR
10.
Blood ; 100(8): 3041-4, 2002 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-12351420

RESUMEN

Clinical resistance to imatinib mesylate is commonly observed in patients with advanced Philadelphia chromosome- positive (Ph(+)) leukemias. Acquired resistance is typically associated with reactivation of BCR-ABL due to kinase domain mutations or gene amplification, indicating that BCR-ABL remains a viable target for inhibition in these patients. Strategies for overcoming resistance can be envisioned through exploitation of other molecular features of the BCR-ABL protein, such as its dependence on the molecular chaperone heat shock protein 90 (Hsp90). To determine whether inhibition of Hsp90 could induce degradation of imatinib mesylate-resistant, mutant BCR-ABL proteins, hematopoietic cells expressing 2 mutant BCR-ABL proteins found in imatinib mesylate-resistant patients (T315I and E255K) were examined for sensitivity to geldanamycin and 17-allylaminogeldanamycin (17-AAG). Both compounds induced the degradation of wild-type and mutant BCR-ABL and inhibited cell growth, with a trend indicating more potent activity against mutant BCR-ABL proteins. These data support clinical investigations of 17-AAG in imatinib mesylate-resistant Ph(+) leukemias.


Asunto(s)
Antineoplásicos/toxicidad , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/genética , Proteínas HSP90 de Choque Térmico/fisiología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Piperazinas/toxicidad , Mutación Puntual , Pirimidinas/toxicidad , Benzamidas , Proteínas HSP90 de Choque Térmico/efectos de los fármacos , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA