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1.
Cancer Gene Ther ; 22(9): 438-44, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26272026

RESUMO

Oncolytic measles virus (MV) strains have demonstrated broad spectrum preclinical anti-tumor efficacy, including breast cancer. Aurora A kinase controls mitotic spindle formation and has a critical role in malignant transformation. We hypothesized that the Aurora A kinase inhibitor MLN8237 (alisertib) can increase MV oncolytic effect and efficacy by causing mitotic arrest. Alisertib enhanced MV oncolysis in vitro and significantly improved outcome in vivo against breast cancer xenografts. In a disseminated MDA-231-lu-P4 lung metastatic model, the MV/alisertib combination treatment markedly increased median survival to 82.5 days with 20% of the animals being long-term survivors versus 48 days median survival for the control animals. Similarly, in a pleural effusion model of advanced breast cancer, the MV/alisertib combination significantly improved outcome with a 74.5 day median survival versus the single agent groups (57 and 40 days, respectively). Increased viral gene expression and IL-24 upregulation were demonstrated, representing possible mechanisms for the observed increase in anti-tumor effect. Inhibiting Aurora A kinase with alisertib represents a novel approach to enhance MV-mediated oncolysis and antitumor effect. Both oncolytic MV strains and alisertib are currently tested in clinical trials, this study therefore provides the basis for translational applications of this combinatorial strategy in the treatment of patients with advanced breast cancer.


Assuntos
Antineoplásicos/uso terapêutico , Aurora Quinase B/antagonistas & inibidores , Azepinas/uso terapêutico , Neoplasias da Mama/terapia , Vírus do Sarampo , Terapia Viral Oncolítica , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Animais , Aurora Quinase B/fisiologia , Azepinas/farmacologia , Proteínas de Bactérias/genética , Neoplasias da Mama/patologia , Chlorocebus aethiops , Terapia Combinada , Feminino , Regulação da Expressão Gênica , Humanos , Cadeias lambda de Imunoglobulina/genética , Interleucinas/biossíntese , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Camundongos , Camundongos Nus , Pirimidinas/farmacologia , Transgenes , Células Vero , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Oncogene ; 34(4): 506-15, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-24469035

RESUMO

Progesterone and estrogen are important drivers of breast cancer proliferation. Herein, we probed estrogen receptor-α (ER) and progesterone receptor (PR) cross-talk in breast cancer models. Stable expression of PR-B in PR-low/ER+ MCF7 cells increased cellular sensitivity to estradiol and insulin-like growth factor 1 (IGF1), as measured in growth assays performed in the absence of exogenous progestin; similar results were obtained in PR-null/ER+ T47D cells stably expressing PR-B. Genome-wide microarray analyses revealed that unliganded PR-B induced robust expression of a subset of estradiol-responsive ER target genes, including cathepsin-D (CTSD). Estradiol-treated MCF7 cells stably expressing PR-B exhibited enhanced ER Ser167 phosphorylation and recruitment of ER, PR and the proline-, glutamate- and leucine-rich protein 1 (PELP1) to an estrogen response element in the CTSD distal promoter; this complex co-immunoprecipitated with IGF1 receptor (IGFR1) in whole-cell lysates. Importantly, ER/PR/PELP1 complexes were also detected in human breast cancer samples. Inhibition of IGF1R or phosphoinositide 3-kinase blocked PR-B-dependent CTSD mRNA upregulation in response to estradiol. Similarly, inhibition of IGF1R or PR significantly reduced ER recruitment to the CTSD promoter. Stable knockdown of endogenous PR or onapristone treatment of multiple unmodified breast cancer cell lines blocked estradiol-mediated CTSD induction, inhibited growth in soft agar and partially restored tamoxifen sensitivity of resistant cells. Further, combination treatment of breast cancer cells with both onapristone and IGF1R tyrosine kinase inhibitor AEW541 was more effective than either agent alone. In summary, unliganded PR-B enhanced proliferative responses to estradiol and IGF1 via scaffolding of ER-α/PELP1/IGF1R-containing complexes. Our data provide a strong rationale for targeting PR in combination with ER and IGF1R in patients with luminal breast cancer.


Assuntos
Neoplasias da Mama/patologia , Proteínas Correpressoras/fisiologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/fisiologia , Receptores de Progesterona/fisiologia , Fatores de Transcrição/fisiologia , Neoplasias da Mama/tratamento farmacológico , Catepsina D/genética , Proliferação de Células/efeitos dos fármacos , Proteínas Correpressoras/análise , DNA/metabolismo , Feminino , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Células MCF-7 , Fosfatidilinositol 3-Quinases/fisiologia , Estrutura Terciária de Proteína , Receptor Cross-Talk/fisiologia , Receptor IGF Tipo 1/fisiologia , Receptores de Progesterona/química , Tamoxifeno/uso terapêutico , Fatores de Transcrição/análise , Transcrição Gênica
3.
Leukemia ; 28(1): 15-33, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23778311

RESUMO

Glycogen synthase kinase-3 (GSK-3) is well documented to participate in a complex array of critical cellular processes. It was initially identified in rat skeletal muscle as a serine/threonine kinase that phosphorylated and inactivated glycogen synthase. This versatile protein is involved in numerous signaling pathways that influence metabolism, embryogenesis, differentiation, migration, cell cycle progression and survival. Recently, GSK-3 has been implicated in leukemia stem cell pathophysiology and may be an appropriate target for its eradication. In this review, we will discuss the roles that GSK-3 plays in hematopoiesis and leukemogenesis as how this pivotal kinase can interact with multiple signaling pathways such as: Wnt/ß-catenin, phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/extracellular signal-regulated kinase (ERK), Notch and others. Moreover, we will discuss how targeting GSK-3 and these other pathways can improve leukemia therapy and may overcome therapeutic resistance. In summary, GSK-3 is a crucial regulatory kinase interacting with multiple pathways to control various physiological processes, as well as leukemia stem cells, leukemia progression and therapeutic resistance. GSK-3 and Wnt are clearly intriguing therapeutic targets.


Assuntos
Carcinogênese , Quinase 3 da Glicogênio Sintase/metabolismo , Hematopoese , Leucemia/patologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Humanos , Leucemia/enzimologia , Leucemia/metabolismo , Leucemia/terapia
4.
Oncogene ; 33(5): 599-610, 2014 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-23334326

RESUMO

In this study, we demonstrate that constitutive activation of Raf-1 oncogenic signaling induces stabilization and accumulation of Aurora-A mitotic kinase that ultimately drives the transition from an epithelial to a highly invasive mesenchymal phenotype in estrogen receptor α-positive (ERα(+)) breast cancer cells. The transition from an epithelial- to a mesenchymal-like phenotype was characterized by reduced expression of ERα, HER-2/Neu overexpression and loss of CD24 surface receptor (CD24(-/low)). Importantly, expression of key epithelial-to-mesenchymal transition (EMT) markers and upregulation of the stemness gene SOX2 was linked to acquisition of stem cell-like properties such as the ability to form mammospheres in vitro and tumor self-renewal in vivo. Moreover, aberrant Aurora-A kinase activity induced phosphorylation and nuclear translocation of SMAD5, indicating a novel interplay between Aurora-A and SMAD5 signaling pathways in the development of EMT, stemness and ultimately tumor progression. Importantly, pharmacological and molecular inhibition of Aurora-A kinase activity restored a CD24(+) epithelial phenotype that was coupled to ERα expression, downregulation of HER-2/Neu, inhibition of EMT and impaired self-renewal ability, resulting in the suppression of distant metastases. Taken together, our findings show for the first time the causal role of Aurora-A kinase in the activation of EMT pathway responsible for the development of distant metastases in ERα(+) breast cancer cells. Moreover, this study has important translational implications because it highlights the mitotic kinase Aurora-A as a novel promising therapeutic target to selectively eliminate highly invasive cancer cells and improve the disease-free and overall survival of ERα(+) breast cancer patients resistant to conventional endocrine therapy.


Assuntos
Aurora Quinase A/metabolismo , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal/genética , Receptor alfa de Estrogênio/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase A/genética , Neoplasias da Mama/enzimologia , Antígeno CD24/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Receptor alfa de Estrogênio/biossíntese , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases/genética , Células MCF-7 , Camundongos , Camundongos Nus , Metástase Neoplásica , Transplante de Neoplasias , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Fosforilação/genética , Proteínas Proto-Oncogênicas c-raf/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Receptor ErbB-2/biossíntese , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Proteína Smad5/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Oncogene ; 27(28): 3901-11, 2008 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-18264135

RESUMO

In this study, we establish an MCF-7 xenograft model that mimics the progression of human breast carcinomas typified by loss of p53 integrity, development of centrosome amplification, acquired estrogen receptor (ERalpha) heterogeneity, overexpression of Mdm2 and metastatic spread from the primary tumor to distant organs. MCF-7 cells with abrogated p53 function (vMCF-7(Dnp53)) maintained nuclear ERalpha expression and normal centrosome characteristics in vitro. However, following mitogen stimulation, they developed centrosome amplification and a higher frequency of aberrant mitotic spindles. Centrosome amplification was dependent on cdk2/cyclin activity since treatment with the small molecule inhibitor SU9516 suppressed centriole reduplication. In contrast to the parental MCF-7 cells, when introduced into nude mice as xenografts, tumors derived from the vMCF-7(DNp53) cell line developed a strikingly altered phenotype characterized by increased tumor growth, higher tumor histopathology grade, centrosome amplification, loss of nuclear ERalpha expression, increased expression of Mdm-2 oncoprotein and resistance to the antiestrogen tamoxifen. Importantly, while MCF-7 xenografts did not develop distant metastases, primary tumors derived from vMCF-7(DNp53) cells gave rise to lung metastases. Taken together, these observations indicate that abrogation of p53 function and consequent deregulation of the G1/S cell cycle transition leads to centrosome amplification responsible for breast cancer progression.


Assuntos
Centrossomo/ultraestrutura , Receptor alfa de Estrogênio/metabolismo , Proteína Supressora de Tumor p53/fisiologia , Animais , Ciclo Celular , Linhagem Celular Tumoral , Núcleo Celular , Genes p53 , Humanos , Camundongos , Camundongos Nus , Metástase Neoplásica , Transplante de Neoplasias , Fenótipo , Fuso Acromático
6.
Ital J Anat Embryol ; 106(2 Suppl 1): 103-10, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11729945

RESUMO

Centrosome duplication plays an important role in genomic stability through bipolar spindle formation and equal chromosome segregation during mitosis. Defects in centrosome duplication and centrosome amplification correlate with aggressive tumors and aneuploidy. Cyclin-dependent cell cycle regulators play a key role in signaling centrosome duplication and the tumor suppressor genes p53, BRCA1 and BRCA2 are suspected to function at mitotic checkpoints that monitor centrosome duplication. The relationship between loss of hormone dependence in breast cancer, and signaling of centrosome duplication in tumor progression is not known. We have developed a MCF-7 cell line expressing GFP-centrin that allows direct visualization of centriole duplication during the cell cycle in living cells. GFP-centrin is expressed and selectively incorporated into the structure of both centrioles making them clearly visible in living cells. Our studies demonstrate three important aspects of recombinant GFP-centrin incorporation into centrioles. 1) GFP-centrin transfected cells grow normally in culture and show no adverse effect associated with GFP-centrin expression; 2) newly duplicated centrioles incorporate centrin during their genesis; and 3) GFP-centrin incorporation into centrioles does not grossly affect cell cycle progression, or centrosome function.


Assuntos
Aneuploidia , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Proteínas de Ligação ao Cálcio/genética , Ciclo Celular/genética , Centríolos/genética , Indicadores e Reagentes/metabolismo , Proteínas Luminescentes/genética , Neoplasias da Mama/metabolismo , Feminino , Imunofluorescência , Proteínas de Fluorescência Verde , Humanos , Modelos Biológicos , Células Tumorais Cultivadas
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