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1.
Cancer Cell ; 5(6): 607-16, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15193263

RESUMO

Tamoxifen significantly reduces tumor recurrence in certain patients with early-stage estrogen receptor-positive breast cancer, but markers predictive of treatment failure have not been identified. Here, we generated gene expression profiles of hormone receptor-positive primary breast cancers in a set of 60 patients treated with adjuvant tamoxifen monotherapy. An expression signature predictive of disease-free survival was reduced to a two-gene ratio, HOXB13 versus IL17BR, which outperformed existing biomarkers. Ectopic expression of HOXB13 in MCF10A breast epithelial cells enhances motility and invasion in vitro, and its expression is increased in both preinvasive and invasive primary breast cancer. The HOXB13:IL17BR expression ratio may be useful for identifying patients appropriate for alternative therapeutic regimens in early-stage breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proteínas de Homeodomínio/genética , Interleucina-17/genética , Tamoxifeno/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/biossíntese , Humanos , Hibridização In Situ , Interleucina-17/biossíntese , Modelos Logísticos , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do Tratamento
2.
Clin Cancer Res ; 13(21): 6327-34, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17975144

RESUMO

PURPOSE: We previously identified three genes, HOXB13, IL17BR, and CHDH, that strongly predict clinical outcome in estrogen receptor (ER)-positive breast cancer patients receiving tamoxifen monotherapy. The biological mechanisms linking these genes to estrogen signaling and tamoxifen response in breast cancer remain to be determined. EXPERIMENTAL DESIGN: In a consecutive series of 148 ER-positive and ER-negative breast cancers, HOXB13, IL17BR, and CHDH gene expression was measured by quantitative real-time PCR and correlated with ER, PR, and HER2 expression. The role of estrogen and ER in the regulation of these three genes was assessed in several ER-positive and ER-negative breast cancer cell lines. RESULTS: In primary breast tumors, HOXB13 expression correlated negatively, and IL17BR and CHDH expression correlated positively, with ER status, and all three genes exhibited an ER-dependent correlation pattern with HER2 status that differs from PR and PS2, two canonical estrogen-regulated genes. Results using breast cancer cell lines show that these genes are regulated by estradiol in an ER-dependent manner, and that this regulation is abrogated by tamoxifen. CONCLUSIONS: HOXB13, IL17BR, and CHDH are estrogen-regulated genes, but their pattern of correlation with known positive (ER, PR) and negative (HER2) predictors of tamoxifen response differs from canonical ER signature genes. These results provide a biological rationale for the prognostic utility of these three genes in early-stage ER-positive breast cancer and for their potential to predict anti-estrogen resistance.


Assuntos
Neoplasias da Mama/metabolismo , Colina Desidrogenase/biossíntese , Colina Desidrogenase/genética , Estrogênios/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Receptores de Interleucina/biossíntese , Receptores de Interleucina/genética , Linhagem Celular , Estudos de Coortes , Humanos , Imuno-Histoquímica/métodos , Progesterona/metabolismo , Prognóstico , RNA/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Interleucina-17 , Tamoxifeno/farmacologia
3.
Cancer Res ; 66(7): 3452-5, 2006 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-16585167

RESUMO

In a screen for gene copy number alterations in mouse mammary tumors initiated by loss of the Brca1 and Trp53 genes, we observed that the majority (11 of 15; 73%) had high-level amplification of wild-type Met, encoding a growth factor receptor implicated in tumor progression. Met amplification was localized to unstable double minute chromosomes and was uniquely found in mouse breast tumors driven by loss of Brca1 and Trp53. Whereas analogous MET amplification was not found in human breast cancers, the identification of a dominant somatic genetic lesion in the Brca1/Trp53 mouse model suggests that recurrent secondary hits may also exist in BRCA1-initiated human breast cancer.


Assuntos
Genes BRCA1 , Neoplasias Mamárias Experimentais/genética , Proteínas Proto-Oncogênicas c-met/genética , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Amplificação de Genes , Deleção de Genes , Camundongos
4.
Clin Cancer Res ; 12(14 Pt 1): 4283-7, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16857803

RESUMO

PURPOSE: Specific activating mutations within the epidermal growth factor receptor (EGFR) identify a subset of non-small cell lung cancers with dramatic sensitivity to the specific tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Despite the abundant expression of EGFR protein in a broad range of epithelial cancers, EGFR mutations have not been reported in a substantial fraction of other cancers. Given recent reports of TKI-responsive cases of esophageal and pancreatic cancer, this study was designed to determine the prevalence of EGFR mutations in these gastrointestinal cancers. EXPERIMENTAL DESIGN: We sequenced exons 18 to 21 of EGFR from 21 cases of Barrett's esophagus, 5 cases of high-grade esophageal dysplasia, 17 cases of esophageal adenocarcinoma, and 55 cases of pancreatic adenocarcinoma. Subsets of esophageal (n = 7) and pancreatic cancer cases (n = 5) were obtained from patients who were subsequently treated with gefitinib or erlotinib-capecitabine, respectively. RESULTS: Mutations of EGFR were identified in two esophageal cancers (11.7%), three cases of Barrett's esophagus (14.2%), and two pancreatic cancers (3.6%). The mutations consisted of the recurrent missense L858R and in-frame deletion delE746-A750, previously characterized as activating EGFR mutations in non-small cell lung cancer. We also identified the TKI drug resistance-associated EGFR T790M mutation in an untreated case of Barrett's esophagus and the corresponding adenocarcinoma. CONCLUSION: The presence of activating mutations within EGFR in both esophageal and pancreatic adenocarcinomas defines a previously unrecognized subset of gastrointestinal tumors in which EGFR signaling may play an important biological role. EGFR mutations in premalignant lesions of Barrett's esophagus also point to these as an early event in transformation of the esophageal epithelium. The role of genotype-directed TKI therapy should be tested in prospective clinical trials.


Assuntos
Adenocarcinoma/genética , Receptores ErbB/química , Receptores ErbB/genética , Neoplasias Esofágicas/genética , Mutação , Neoplasias Pancreáticas/genética , Adenocarcinoma/metabolismo , Antineoplásicos/farmacologia , Transformação Celular Neoplásica , Análise Mutacional de DNA , Éxons , Genótipo , Humanos , Estrutura Terciária de Proteína
5.
J Clin Oncol ; 23(31): 8081-92, 2005 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16204011

RESUMO

PURPOSE: Most cases of non-small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib. PATIENTS AND METHODS: We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC. RESULTS: EGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46%) with an EGFR mutation, two of seven tumors (29%) with amplification, and five of 56 tumors (9%) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFR genotype. CONCLUSION: EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Amplificação de Genes , Neoplasias Pulmonares/genética , Mutação , Quinazolinas/uso terapêutico , Adulto , Idoso , Antineoplásicos , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Gefitinibe , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Taxa de Sobrevida
6.
Clin Cancer Res ; 11(22): 8105-8, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16299242

RESUMO

PURPOSE: Small-molecule tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) have shown modest yet reproducible response rates in patients with squamous cell carcinoma of the head and neck (SCCHN). Somatic mutations in EGFR have recently been shown to be predictive of a clinical response in patients with non-small cell lung cancer (NSCLC) treated with these inhibitors. The objective of this study was to determine if such mutations, or recently reported mutations in ERBB2, also underlie EGFR-TKI responsiveness in SCCHN patients. EXPERIMENTAL DESIGN: We sequenced the kinase domain of EGFR and exon 20 of ERBB2 in tumor specimens from eight responsive patients. In addition, mutational analysis was done on tumor specimens from nine gefitinib nonresponders and 65 unselected cases of SCCHN. RESULTS: None of eight TKI-responsive specimens had mutations within the kinase domain of EGFR. EGFR amplification was also not associated with drug responsiveness. However, a single responsive case had a somatic missense mutation within exon 20 of ERBB2. CONCLUSION: Our data indicate that unlike NSCLC, EGFR kinase mutations are rare in unselected cases of SCCHN within the United States and are not linked to gefitinib or erlotinib responses in SCCHN. Alternative mechanisms, including ERBB2 mutations, may underlie responsiveness in this tumor type.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Mutação/genética , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/genética , Idoso , Antineoplásicos/uso terapêutico , Sequência de Bases , Carcinoma de Células Escamosas/genética , Análise Mutacional de DNA , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Pessoa de Meia-Idade , Quinazolinas/uso terapêutico , Resultado do Tratamento
7.
J Immunol ; 179(1): 195-200, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17579038

RESUMO

NF-kappaB1 and Notch2 are both required for the development of marginal zone (MZ) B cells. Analysis of B lymphocyte development in mice that are doubly heterozygous at the Notch2 and NF-kappaB1 loci revealed synergism between Notch2 and NF-kappaB1 during MZ B cell development. Two known transcriptional targets of the Notch pathway, Hes-5 and Deltex-1, were found to be preferentially expressed in MZ B cells and regulated by NF-kappaB1. These studies provide in vivo evidence for a genetic interaction between the Notch and NF-kappaB pathways.


Assuntos
Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Comunicação Celular/imunologia , Diferenciação Celular/imunologia , Subunidade p50 de NF-kappa B/fisiologia , Receptor Notch2/fisiologia , Baço/imunologia , Baço/metabolismo , Tirosina Quinase da Agamaglobulinemia , Animais , Subpopulações de Linfócitos B/enzimologia , Subpopulações de Linfócitos B/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Comunicação Celular/genética , Diferenciação Celular/genética , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Ativação Enzimática/imunologia , Regulação da Expressão Gênica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Subunidade p50 de NF-kappa B/deficiência , Subunidade p50 de NF-kappa B/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Transdução de Sinais/imunologia , Baço/patologia , Ubiquitina-Proteína Ligases
8.
Proc Natl Acad Sci U S A ; 104(43): 17093-8, 2007 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-17942676

RESUMO

Deregulated expression of HOXB13 in a subset of estrogen receptor-positive breast cancer patients treated with tamoxifen monotherapy is associated with an aggressive clinical course and poor outcome. Because the ovary is another hormone-responsive organ, we investigated whether HOXB13 plays a role in ovarian cancer progression. We show that HOXB13 is expressed in multiple human ovarian cancer cell lines and tumors and that knockdown of endogenous HOXB13 by RNA interference in human ovarian cancer cell lines is associated with reduced cell proliferation. Ectopic expression of HOXB13 is capable of transforming p53(-/-) mouse embryonic fibroblasts and promotes cell proliferation and anchorage-independent growth in mouse ovarian cancer cell lines that contain genetic alterations in p53, myc, and ras. In this genetically defined cell line model of ovarian cancer, we demonstrate that HOXB13 collaborates with activated ras to markedly promote tumor growth in vivo and that HOXB13 confers resistance to tamoxifen-mediated apoptosis. Taken together, our results support a pro-proliferative and pro-survival role for HOXB13 in ovarian cancer.


Assuntos
Proteínas de Homeodomínio/metabolismo , Neoplasias Ovarianas/patologia , Animais , Apoptose/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Progressão da Doença , Estradiol/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Neoplasias Ovarianas/genética , Fuso Acromático/efeitos dos fármacos , Fuso Acromático/metabolismo , Fuso Acromático/patologia , Tamoxifeno/farmacologia
9.
Genes Dev ; 21(17): 2131-6, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17704304

RESUMO

The neural crest (NC) is a highly motile cell population that gives rise to multiple tissue lineages during vertebrate embryogenesis. Here, we identify a novel effector of the small GTPase Rap, called RADIL, and show that it is required for cell adhesion and migration. Knockdown of radil in the zebrafish model results in multiple defects in NC-derived lineages such as cartilage, pigment cells, and enteric neurons. We specifically show that these defects are primarily due to the diminished migratory capacity of NC cells. The identification of RADIL as a regulator of NC migration defines a role for the Rap pathway in this process.


Assuntos
Proteínas de Transporte/fisiologia , Adesão Celular/genética , Movimento Celular/genética , Genes vpr , Morfogênese/genética , Crista Neural/embriologia , Proteínas de Peixe-Zebra/fisiologia , Proteínas rap de Ligação ao GTP/fisiologia , Animais , Animais Geneticamente Modificados , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento , Genes ras
10.
Proc Natl Acad Sci U S A ; 103(50): 18969-74, 2006 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-17142318

RESUMO

The process of invasion and metastasis during tumor progression is often reminiscent of cell migration events occurring during embryonic development. We hypothesized that genes controlling cellular changes in the Spemann organizer at gastrulation might be reactivated in tumors. The Goosecoid homeobox transcription factor is a known executer of cell migration from the Spemann organizer. We found that indeed Goosecoid is overexpressed in a majority of human breast tumors. Ectopic expression of Goosecoid in human breast cells generated invasion-associated cellular changes, including an epithelial-mesenchymal transition. TGF-beta signaling, known to promote metastasis, induced Goosecoid expression in human breast cells. Moreover, Goosecoid significantly enhanced the ability of breast cancer cells to form pulmonary metastases in mice. These results demonstrate that Goosecoid promotes tumor cell malignancy and suggest that other conserved organizer genes may function similarly in human cancer.


Assuntos
Proteína Goosecoid/metabolismo , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Organizadores Embrionários/metabolismo , Envelhecimento/fisiologia , Animais , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Diferenciação Celular , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Cães , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteína Goosecoid/genética , Humanos , Camundongos , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
11.
Proc Natl Acad Sci U S A ; 103(33): 12405-10, 2006 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16894141

RESUMO

In a screen for gene copy-number changes in mouse mammary tumors, we identified a tumor with a small 350-kb amplicon from a region that is syntenic to a much larger locus amplified in human cancers at chromosome 11q22. The mouse amplicon contains only one known gene, Yap, encoding the mammalian ortholog of Drosophila Yorkie (Yki), a downstream effector of the Hippo(Hpo)-Salvador(Sav)-Warts(Wts) signaling cascade, recently identified in flies as a critical regulator of cellular proliferation and apoptosis. In nontransformed mammary epithelial cells, overexpression of human YAP induces epithelial-to-mesenchymal transition, suppression of apoptosis, growth factor-independent proliferation, and anchorage-independent growth in soft agar. Together, these observations point to a potential oncogenic role for YAP in 11q22-amplified human cancers, and they suggest that this highly conserved signaling pathway identified in Drosophila regulates both cellular proliferation and apoptosis in mammalian epithelial cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cromossomos Humanos Par 11 , Oncogenes , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose/fisiologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Forma Celular , Transformação Celular Neoplásica , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Glândulas Mamárias Humanas/citologia , Camundongos , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Transdução de Sinais/fisiologia , Transativadores/genética , Transativadores/metabolismo , Proteínas de Sinalização YAP
12.
Proc Natl Acad Sci U S A ; 103(7): 2316-21, 2006 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-16461907

RESUMO

The success of molecular targeted therapy in cancer may depend on the selection of appropriate tumor types whose survival depends on the drug target, so-called "oncogene addiction." Preclinical approaches to defining drug-responsive subsets are needed if initial clinical trials are to be directed at the most susceptible patient population. Here, we show that gastric cancer cells with high-level stable chromosomal amplification of the growth factor receptor MET are extraordinarily susceptible to the selective inhibitor PHA-665752. Although MET activation has primarily been linked with tumor cell migration and invasiveness, the amplified wild-type MET in these cells is constitutively activated, and its continued signaling is required for cell survival. Treatment with PHA-665752 triggers massive apoptosis in 5 of 5 gastric cancer cell lines with MET amplification but in 0 of 12 without increased gene copy numbers (P = 0.00016). MET amplification may thus identify a subset of epithelial cancers that are uniquely sensitive to disruption of this pathway and define a patient group that is appropriate for clinical trials of targeted therapy using MET inhibitors.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Amplificação de Genes , Indóis/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Receptores de Fatores de Crescimento/genética , Neoplasias Gástricas/genética , Sulfonas/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular , Testes Genéticos , Humanos , Proteínas Proto-Oncogênicas c-met , Neoplasias Gástricas/enzimologia
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