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1.
Int J Oncol ; 41(2): 611-20, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22581300

RESUMO

Docetaxel is one of the most commonly used chemotherapeutic agents in breast cancer. To avert from significant toxicities with no clinical benefit, identification of predictive markers for response is one of the most important unsolved clinical needs. Therefore, the potential associations of RASSF1A hypermethylation and response to docetaxel-based chemotherapy were evaluated, and the underlying mechanism was studied. The expression of RASSF1A in breast cancer cell lines and tissues of normal breast, ductal carcinoma in situ (DCIS), and breast cancer (n=45) was analyzed by immunohistochemistry and western blot analysis. Immunohistochemical staining showed that the expression of RASSF1A was frequently lost in primary breast cancers and human breast cancer cell lines, while normal breast tissues or DCIS displayed moderate to strong expression. Furthermore, quantitative methylation analysis of the RASSF1A promoter region in 45 primary breast cancers revealed that RASSF1A was frequently methylated in primary breast cancers (≥20% methylation in 53% of the patients), and prospective analysis in patients with locally advanced or recurrent breast cancer showed that the mean level of methylation of RASSF1A was significantly higher in patients who did not respond to docetaxel-based chemotherapy (30.6±8.5%) than patients with partial or complete response (20.1±11.2%, p=0.042). Finally, in vitro studies showed that RASSF1A had cooperative activity in suppression of cancer cell growth and proliferation by enhancing docetaxel-induced cell cycle arrest. Our results suggest that hypermethylated RASSF1A is an important modulating factor for the efficacy of docetaxel-based chemotherapy in breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Metilação de DNA , Neoplasias Ductais, Lobulares e Medulares/tratamento farmacológico , Regiões Promotoras Genéticas , Taxoides/farmacologia , Moduladores de Tubulina/farmacologia , Proteínas Supressoras de Tumor/genética , Adulto , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sequência de Bases , Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Docetaxel , Regulação para Baixo , Epigênese Genética , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Logísticos , Análise Multivariada , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Análise de Sequência de DNA , Taxoides/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Proteínas Supressoras de Tumor/metabolismo
2.
Ann Oncol ; 21(5): 942-8, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-19840953

RESUMO

BACKGROUND: Patients with breast cancer brain metastasis are a heterogeneous group in relation to tumor biology and outcome. MATERIALS AND METHODS: The group of 222 breast cancer patients with brain metastasis was divided into three biological subgroups. The propensity of biological subtypes for metastases to the brain and survivals depending on biological subtype, recursive partitioning analysis of Radiation Therapy Oncology Group (RPA RTOG) prognostic class and the use of systemic treatment after whole-brain radiotherapy were assessed. RESULTS: The rate of patients with triple-negative, human epidermal growth factor receptor 2 (HER2)-positive and luminal breast cancer with brain metastases was 28%, 53% and 19%, respectively. Median survival from brain metastases in triple-negative, HER2-positive and luminal subtype was 3.7, 9 and 15 months, respectively. Median survival from brain metastases in RPA RTOG prognostic class I, II and III was 15, 11 and 3 months, respectively. In the luminal and in the triple-negative subtype, systemic therapy prolonged survival from 3 to 14 months and from 3 to 4 months, respectively. In HER2-positive subtype, median survival without further treatment, after chemotherapy and after chemotherapy with targeted therapy were 3, 8 and 11 months, respectively. CONCLUSIONS: HER2-positive and triple-negative breast cancers have special predilection for metastases to the brain. Survival from brain metastases depended on performance status and the use of systemic treatment.


Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Irradiação Craniana , Neoplasias Ductais, Lobulares e Medulares/mortalidade , Adulto , Idoso , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/radioterapia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neoplasias Ductais, Lobulares e Medulares/radioterapia , Neoplasias Ductais, Lobulares e Medulares/secundário , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
3.
Breast Cancer Res Treat ; 116(3): 471-8, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18686028

RESUMO

FEZ1/LZTS1 is a tumor suppressor gene located in chromosomal band 8p22, and methylation has been identified as a mechanism for its loss of function in tumors. Chromosomal deletion at 8p22 is also frequent in breast cancer. We therefore examined whether LZTS1 plays a role in breast cancer. We analyzed expression of LZTS1 at both the RNA and protein levels, and promoter methylation in a number of primary tumors and cell lines from breast cancer. We also examined the association between LZTS1 expression and different clinicopathological parameters of breast cancer. We found that the expression of LZTS1 mRNA was reduced in 25 of 50 (50%) primary tumors and 29 of 30 (97%) breast cancer cell lines. Immunohistochemical staining showed that LZTS1 protein was absent or down-regulated in 72 (72%) of 100 primary breast carcinomas. Reduced expression of LZTS1 at either the RNA or protein level was significantly correlated with lymph node metastases (P < 0.05). DNA methylation analysis revealed that the LZTS1 gene was frequently methylated in both cell lines and primary tumors from breast cancer, and the extent of DNA methylation was correlated with reduced expression of the gene. These findings suggest that LZTS1 plays a role in the development and progression of breast cancer at least through promoter methylation-mediated transcriptional downregulation.


Assuntos
Neoplasias da Mama/genética , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Papilar/genética , Metilação de DNA , Neoplasias Ductais, Lobulares e Medulares/genética , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/secundário , Carcinoma Papilar/metabolismo , Carcinoma Papilar/secundário , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Ilhas de CpG , Primers do DNA/química , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neoplasias Ductais, Lobulares e Medulares/secundário , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas
4.
Breast Cancer ; 14(4): 381-7, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17986803

RESUMO

BACKGROUND: Lymphatic vessel invasion (LVI) has been conventionally assessed on hematoxylin-eosin (HE) stained sections, but this assessment tends to be subjective. The aim of this study is to investigate the significance of LVI in invasive breast cancers, primarily using immunohistochemical lymphatic endothelial markers. METHODS: We studied 69 invasive breast carcinoma cases. Using D2-40 and podoplanin, we investigated the distribution of lymphatic vessels around the tumor and LVI, and they were compared with the HE sections. The correlation between LVI, lymph node metastasis and disease free survival (DFS) was also investigated. RESULTS: Lymphatic vessels were most frequently seen outside the tumor (86%), whereas lymphatic vessels were not seen in the central zone of the tumor. LVI was found in 22 cases, of which nineteen was seen in the peripheral zone (87%). For both HE and lymphatic markers, the rates of mild LVI tended to be high. The concordance rate between D2-40 and podoplanin was 94.2% (65/69). LVI assessed on HE sections was corresponded to 54/69 cases (78.2%) using either D2-40 or podoplanin. There were 25 axillary lymph node positive cases. Lymph node metastasis significantly correlated with LVI assessed by HE section, but did not correlate with LVI assessed by the lymphatic markers. The tumor recurred in 19 cases during the mean follow-up period of 47.5 months. Disease free survival was significantly better for LVI negative cases on HE analysis, and LVI negative or mildly positive by any staining procedure. CONCLUSION: The lymphatic endothelium markers, D2-40 and podoplanin, are very useful for detecting LVI, but careful examination by routine HE sections may be enough for routine practice. Moderate or marked degree of LVI may be of value to predict survival.


Assuntos
Adenocarcinoma Mucinoso/patologia , Neoplasias da Mama/patologia , Endotélio Linfático/patologia , Linfonodos/patologia , Vasos Linfáticos/patologia , Neoplasias Ductais, Lobulares e Medulares/patologia , Adenocarcinoma Mucinoso/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais Murinos , Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Endotélio Linfático/metabolismo , Feminino , Humanos , Técnicas Imunoenzimáticas , Linfonodos/metabolismo , Metástase Linfática , Vasos Linfáticos/metabolismo , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica/diagnóstico , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Prognóstico
5.
Histopathology ; 51(1): 33-9, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17542993

RESUMO

AIMS: There is considerable evidence to link cyclooxygenase (COX)-2 to the development of cancer. The aim of this study was to assess COX-2 expression and its subcellular localization in lobular in situ neoplasia (LIN) of the breast and to verify differences in COX-2 expression between different grades of lesions according to the Tavassoli classification. METHODS AND RESULTS: We analysed the expression of COX-2 protein by immunohistochemistry in tissue samples of 51 LIN lesions classified into three grades according to the Tavassoli classification. COX-2 immunostaining was observed in 78.4% of LIN samples and showed a prevalent membranous rather than cytoplasmic pattern. COX-2 was expressed in 16/17 (94.1%) LIN1, 22/25 (88%) LIN2 and 2/9 (22.2%) LIN3. As regards COX-2 expression, a statistically significant difference was found between LIN1 and LIN3 (P = 0.001) and between LIN2 and LIN3 (P =0.001). No difference was found between LIN1 and LIN2. Moreover, a significant negative correlation was found between LIN grade and COX-2 expression (P < 0.0001). CONCLUSIONS: COX-2 is highly expressed in LIN, supporting a role for this protein in the early stage of breast carcinogenesis, representing the rationale for using COX-2 selective inhibitors in the earliest stages of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Ciclo-Oxigenase 2/metabolismo , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/classificação , Carcinoma Intraductal não Infiltrante/patologia , Ciclo-Oxigenase 2/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Neoplasias Ductais, Lobulares e Medulares/classificação , Neoplasias Ductais, Lobulares e Medulares/patologia
6.
Clin Cancer Res ; 12(5): 1470-8, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16533770

RESUMO

PURPOSE: hMena (ENAH), a cytoskeleton regulatory protein involved in the regulation of cell motility and adhesion, is overexpressed in breast cancer. The aim of this study was to define at what stage of breast carcinogenesis hMena is overexpressed and to correlate hMena overexpression with established prognostic factors in breast cancer, focusing on human epidermal growth factor receptor-2 (HER-2). EXPERIMENTAL DESIGN: hMena expression was assessed immunohistochemically in a prospective cohort of cases (n = 360) encompassing a highly representative spectrum of benign breast diseases associated with different risk of transformation, in situ, invasive, and metastatic tumors. Correlations with conventional pathologic and prognostic variables, such as proliferation index, hormonal receptor status, and HER-2 overexpression, were also evaluated. In vitro experiments were done to study the effect of neuregulin-1 and Herceptin treatments on hMena expression. RESULTS: hMena protein is undetectable in normal breast and is weakly expressed in a small percentage of low-risk benign diseases (9%), but displays a progressive and significant increase of positivity in benign lesions at higher risk of transformation (slightly increased risk 43%; moderate increased risk 67%), in in situ (72%), invasive (93%), and metastatic breast cancer (91%). A significant direct correlation with tumor size (P = 0.04), proliferation index (P < 0.0001), and HER-2 overexpression (P < 0.0001) and an inverse relationship with estrogen (P = 0.036) and progesterone receptors (P = 0.001) are found in invasive carcinomas. In vitro experiments show that neuregulin-1 up-regulates, whereas Herceptin down-regulates, hMena expression. CONCLUSIONS: Our data provide new insights into the relevance of actin-binding proteins in human breast carcinogenesis and indicate hMena overexpression as a surrogate indicator in breast disease management.


Assuntos
Neoplasias da Mama/metabolismo , Transformação Celular Neoplásica , Proteínas do Citoesqueleto/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Biomarcadores Tumorais , Mama , Neoplasias da Mama/patologia , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/secundário , Carcinoma Papilar/metabolismo , Carcinoma Papilar/secundário , Proliferação de Células , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neoplasias Ductais, Lobulares e Medulares/secundário , Neuregulina-1/farmacologia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Trastuzumab
7.
Cancer Lett ; 244(2): 203-10, 2006 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-16469432

RESUMO

The aim of this study is to investigate the possible role of inhibitor of DNA binding (Id-1) overexpression in human breast cancer. We examined Id-1 expression by immunohistochemistry in 263 human breast cancers, 15 in situ lesions and 248 invasive cancers to investigate the relationship between its expression and various clinicopathological factors. Id-1 expression was significantly higher in invasive ductal carcinoma than in in situ ductal carcinoma or other invasive cancer subtypes (P=0.029 and 0.006, respectively). We also examined the association between Id-1 expression and tumor angiogenesis by measuring microvessel densities (MVD). Regarding the endothelial cells of microvessels showed negative or very weak Id-1 expression, Id-1 overexpression was found to be significantly related to MVD (P=0.014). Furthermore, Id-1 overexpression was found to be significantly associated with higher MVD in the ER-negative and node-involved subgroups of breast cancer (P=0.040 and 0.046, respectively). These data indicate that Id-1 overexpression is significantly associated with tumor angiogenesis, especially in the ER-negative and node-positive subtypes of invasive breast cancer. Thus, Id-1 presents a possible therapeutic antitumor target molecule in ER-negative and node-positive breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Proteína 1 Inibidora de Diferenciação/metabolismo , Linfonodos/patologia , Neovascularização Patológica/metabolismo , Receptores de Estrogênio/metabolismo , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/irrigação sanguínea , Carcinoma Ductal de Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Microcirculação , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasias Ductais, Lobulares e Medulares/irrigação sanguínea , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neoplasias Ductais, Lobulares e Medulares/patologia , Prognóstico , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
8.
Br J Cancer ; 93(9): 1046-52, 2005 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-16175185

RESUMO

Breast cancer is a heterogeneous disease, though little is known about some of its rarer forms, including certain histologic types. Using Surveillance, Epidemiology, and End Results Program data on 135 157 invasive breast cancer cases diagnosed from 1992 to 2001, relationships between nine histologic types of breast cancer and various tumour characteristics were assessed. Among women aged 50-89 years at diagnosis, lobular and ductal/lobular carcinoma cases were more likely to be diagnosed with stage III/IV, > or =5.0 cm, and node-positive tumours compared to ductal carcinoma cases. Mucinous, comedo, tubular, and medullary carcinomas were less likely to present at an advanced stage. Lobular, ductal/lobular, mucinous, tubular, and papillary carcinomas were less likely, and comedo, medullary, and inflammatory carcinomas were more likely to be oestrogen receptor (ER) negative/progesterone receptor (PR) negative and high grade (notably, 68.2% of medullary carcinomas were ER-/PR- vs 19.3% of ductal carcinomas). In general, similar differences were observed among women diagnosed at age 30-49 years. Inflammatory carcinomas are associated with more aggressive tumour phenotypes, and mucinous, tubular, and papillary tumours are associated with less aggressive phenotypes. The histologic types of breast cancer studied here differ greatly in their clinical presentations, and the differences in their hormone receptor profiles and grades point to their likely different aetiologies.


Assuntos
Adenocarcinoma Mucinoso/patologia , Adenocarcinoma/patologia , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Papilar/patologia , Neoplasias Ductais, Lobulares e Medulares/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma Mucinoso/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Papilar/metabolismo , Feminino , Humanos , Linfonodos/patologia , Pessoa de Meia-Idade , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Programa de SEER
9.
Cancer ; 103(11): 2241-51, 2005 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15844176

RESUMO

BACKGROUND: The objective of this study was to assess hormone receptor status as an independent predictor of survival in a population-based cohort of women with breast carcinoma who were followed for up to 11 years. METHODS: Since 1990, the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program has collected data on hormone receptor status among patients with breast carcinoma. In a cohort of 205,736 women with breast carcinoma age > or = 20 years at diagnosis who were entered into the SEER data base between 1990 and 2000, the authors analyzed the association of hormone receptor status with year of diagnosis, patient age, disease stage, tumor histology, tumor grade, race/ethnicity, and metropolitan/statewide residence areas. Kaplan-Meier survival curves were compared according to hormone receptor status, and Cox proportional-hazards regression models were used to assess the association of hormone receptor status with breast carcinoma-specific and all-cause mortality controlling for age, disease stage, tumor grade, tumor histology, race/ethnicity, and SEER region. RESULTS: Women who had tumors that were positive for both estrogen and progesterone hormone receptors had significantly better survival than other women with breast carcinoma in the overall cohort, within each stage, and in the younger and older age groups, although the survival advantage was greater among women age < or = 50 years than among older women. Hormone receptor status was associated with mortality even when patient age, disease stage, tumor grade, tumor histology, race/ethnicity, and metropolitan/statewide residence areas were taken into account. CONCLUSIONS: Hormone receptor status was identified as an independent predictor of outcome in women with breast carcinoma. Data from clinical trials with long follow-up may shed light on whether and how the benefit of hormonal and other treatment varies with hormone receptor status.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidade , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neoplasias Ductais, Lobulares e Medulares/mortalidade , Programa de SEER , Taxa de Sobrevida
10.
Clin Cancer Res ; 11(6): 2222-8, 2005 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-15788670

RESUMO

PURPOSE: RON and MET belong to a subfamily of tyrosine kinase receptors. They both can induce invasive growth, including migration, cell dissociation, and matrix invasion. Cross-linking experiments show that RON and MET form a noncovalent complex on the cell surface and cooperate in intracellular signaling. We wanted to examine the clinical significance of RON and MET expression patterns in node-negative breast cancer. EXPERIMENTAL DESIGN: We studied the protein expressions of RON and MET in five breast cancer cell lines and a homogeneous cohort of 103 T(1-2)N(0)M(0) breast carcinoma patients, including 52 patients with distant metastases and 51 patients with no evidence of disease after at least a 10-year follow-up. RESULTS: Both HCC1937 and MDA-MB-231 cancer cell lines co-overexpressed RON and MET. The MCF-7 cell line did not express RON or MET. In multiple logistic regression analysis, RON expression (odds ratio, 2.6; P = 0.05) and MET expression (odds ratio, 4.7; P = 0.009) were independent predictors of distant relapse. RON+/MET+ and RON-/MET+ tumors resulted in a large risk increase for 10-year disease-free survival after adjusting for tumor size, histologic grade, estrogen receptor, bcl-2, HER-2/neu, and p53 status by multivariate Cox analysis (risk ratio, 5.3; P = 0.001 and risk ratio, 3.76; P = 0.005). The 10-year disease-free survival was 79.3% in patients with RON-/MET- tumors, was only 11.8% in patients with RON+/MET+ tumors, and was 43.9% and 55.6% in patients with RON-/MET+ and RON+/MET- tumors. CONCLUSIONS: Co-expression of RON and MET seems to signify an aggressive phenotype in node-negative breast cancer patients.


Assuntos
Neoplasias da Mama/metabolismo , Linfonodos/patologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Adulto , Idoso , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neoplasias Ductais, Lobulares e Medulares/secundário , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-met , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo
11.
Clin Cancer Res ; 11(2 Pt 1): 520-8, 2005 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-15701836

RESUMO

PURPOSE: The loss of Wnt-5a, a G-protein-coupled receptor ligand, or Syk, an intracellular kinase, has in separate studies been associated with poor prognosis of breast cancer patients. Both proteins are involved in cell adhesion, a key event in epithelial cancer metastasis. Here, we have investigated whether Syk is part of the Wnt-5a/discoidin domain receptor-1 (DDR1) signaling pathway and if a signaling interaction of these proteins is important for breast cancer-specific survival. EXPERIMENTAL DESIGN: The signaling interactions between Wnt-5a/DDR1 and Syk were addressed in mammary cell lines. Their mRNA and protein levels and the respective clinical correlates were investigated in 94 cases of primary breast cancer. RESULTS: The expression of Wnt-5a and Syk correlated in four of five tumor cell lines. However, despite a constitutive association between Syk and the Wnt-5a-dependent adhesion receptor DDR1, we found no evidence of a Wnt-5a/DDR1-mediated activation of Syk. Instead, beta(1) integrins initiate the adhesion-induced activation of Syk. In tumors from breast cancer patients, the protein expression of Wnt-5a and Syk were differently regulated at the translational and transcriptional level, respectively. Analysis of breast cancer-specific survival revealed that the presence of Wnt-5a and Syk in primary tumors has good predictive value for a favorable outcome. Intriguingly, a simultaneous loss of both proteins did not reduce survival more than loss of either. CONCLUSIONS: Despite the difference in regulation of Wnt-5a and Syk protein expression and their lack of signaling interaction, our clinical data indicate that a favorable prognosis in breast cancer requires the expression and signaling activity of both.


Assuntos
Neoplasias da Mama/metabolismo , Precursores Enzimáticos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Adesão Celular/fisiologia , Receptor com Domínio Discoidina 1 , Células Epiteliais/metabolismo , Humanos , Cadeias beta de Integrinas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Invasividade Neoplásica/patologia , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neoplasias Ductais, Lobulares e Medulares/mortalidade , Neoplasias Ductais, Lobulares e Medulares/patologia , Biossíntese de Proteínas , Taxa de Sobrevida , Quinase Syk , Transcrição Gênica , Células Tumorais Cultivadas , Proteínas Wnt , Proteína Wnt-5a
12.
Br J Cancer ; 91(8): 1532-42, 2004 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-15480434

RESUMO

The epidermal growth factor receptor (EGFR) family plays an important role in breast carcinogenesis. Much interest has been focused recently on its members because of their potential role as prognostic indicators in breast cancer and their involvement in cancer therapy. We have evaluated more than 1500 cases of invasive breast carcinoma immunohistochemically using tissue microarray technology to examine the expression of EGFR family receptor proteins. We have found that 20.1 and 31.8% of cases were positive for EGFR and c-erbB-2, respectively, and 45 and 45.1% of tumours overexpressed for c-erbB-3 and c-erbB-4, respectively. The expression of either EGFR or c-erbB-2 was associated with other bad prognostic features and with poor outcome. Neither c-erbB-3 nor c-erbB-4 had any association with survival. c-erbB-2 had an independent prognostic effect on overall and disease-free survival (DFS) in all cases, as well as in the subset of breast carcinoma patients with nodal metastases. Several hetero- and homodimeric combinations have been reported between the EGFR members. Those dimers can evoke diverse signal transduction pathways with variable cellular responses. We stratified cases according to their co-expression of receptors into distinct groups with different receptor-positive combinations. Patients whose tumours co-expressed c-erbB-2 and c-erbB-3, as well as those whose tumours co-expressed EGFR, c-erbB-2 and c-erbB-4 showed an unfavourable outcome compared with other groups, while combined c-erbB-3 and c-erbB-4 expression was associated with a better outcome. In cases showing expression of one family member only (homodimers), we found a significant association between c-erbB-4 homodimer-expressing tumours and better DFS. In contrast, patients with c-erbB-2 homodimer-expressing tumours had a significant poorer DFS compared with other cases. These data imply that the combined profile expression patterns of the four receptor family members together provide more accurate information on the tumour behaviour than studying the expression of each receptor individually.


Assuntos
Neoplasias da Mama/metabolismo , Receptores ErbB/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adolescente , Adulto , Idoso , Neoplasias da Mama/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neoplasias Ductais, Lobulares e Medulares/patologia , Prognóstico , Estudos Prospectivos , Receptor ErbB-4 , Taxa de Sobrevida
13.
Oncol Rep ; 12(4): 755-9, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15375496

RESUMO

Our aim was to study the role of oxidant and nitric oxide (NO)-derived damage in human breast carcinomas by studying the expression of nitrotyrosine in tumor tissue. To elucidate whether nitrotyrosine levels associate with NO synthesis and have an effect on antioxidative enzyme response or angiogenesis, we also studied the expression of all three nitric oxide synthases (NOS), manganese superoxide dismutase (MnSOD), catalase and vascular endothelial growth factor (VEGF) in the tumors. A large set of breast cancer samples in microarray blocks were stained with antibodies to nitrotyrosine, iNOS, eNOS, nNOS, MnSOD, catalase and VEGF. Nitrotyrosine expression was seen in 56% of the cases. There was a close relationship between the expression of nitrotyrosine and all three NOS isoforms (for all p<0.0005), catalase (p<0.0005) and MnSOD (p=0.043), in addition enlarged tumor size was in association with high nitrotyrosine (p=0.046), eNOS (p=0.005) and VEGF (p=0.046) levels. Our findings suggest that NO-derived oxidative damage takes place and its level associates to NOS synthesis in human breast cancer. The current results also imply the attempt of cells to hedge against effects of NO by increasing their MnSOD and catalase expression.


Assuntos
Neoplasias da Mama/metabolismo , Sequestradores de Radicais Livres/farmacologia , Óxido Nítrico/metabolismo , Oxidantes/farmacologia , Estresse Oxidativo , Tirosina/análogos & derivados , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Carcinoma Papilar , Catalase/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neoplasias Ductais, Lobulares e Medulares/patologia , Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/metabolismo , Oxirredução , Isoformas de Proteínas , Superóxido Dismutase/metabolismo , Tirosina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Int J Oncol ; 24(5): 1197-204, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15067342

RESUMO

Our purpose was to determine the respective prognostic significance of CD105 and CD31 immunoexpression in node negative patients with breast carcinoma, since angiogenesis induces blood borne metastases and death in carcinomas. CD105 (endoglin) has been reported as expressed by activated endothelial cells and consequently should better reflect neoangiogenesis in malignant tumors. Comparison of CD31 and CD105 immunocytochemical expression was undertaken in a series of 905 breast carcinomas. Results were compared to patients' long-term (median = 11.3 years) outcome. Univariate (Kaplan-Meier) analysis showed that the number of CD105+ microvessels (cut-off 15 vessels) correlated significantly with poor overall survival (p=0.001). This correlation was less significant in node negative patients (p=0.035). The number of CD31+ microvessels (cut-off 25 vessels) similarly correlated with poor survival (p=0.032) but not in the subgroup of node negative patients. Marked CD105 expression also correlated with a high risk for metastasis in all patients (p=0.0002) and in the subset of node negative patients (p=0.001). Similarly metastasis risk in node negative patients correlated with marked CD31 immunocytochemical expression (p=0.02). Multivariate analysis (Cox model) identified CD105, but not CD31 immunoexpression, as an independent prognostic indicator. Our results suggest that: i) in breast carcinomas, immunoselection of microvessels containing activated CD105 labelled endothelial cells is endowed with a stronger prognostic significance, as compared to CD31 vessels labelling; ii) the CD105 immunoexpression may be considered as a potential tool for selecting node negative patients with a poorer outcome and higher metastasis risk; iii) in these patients specific antiangiogenic therapy targeted by anti-CD105 conjugates can be further developed.


Assuntos
Neoplasias da Mama/irrigação sanguínea , Neoplasias Ductais, Lobulares e Medulares/irrigação sanguínea , Neovascularização Patológica/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Endoglina , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Linfonodos/patologia , Metástase Linfática , Microcirculação , Neoplasias Ductais, Lobulares e Medulares/diagnóstico , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neovascularização Patológica/patologia , Valor Preditivo dos Testes , Prognóstico , Receptores de Superfície Celular , Fatores de Risco , Resultado do Tratamento
15.
J Clin Oncol ; 21(23): 4306-13, 2003 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-14645419

RESUMO

PURPOSE: To test the hypothesis that prognostic information in breast cancer may be derived from an accurate assessment of epithelial cell cycle entry, as indicated by expression of minichromosome maintenance (MCM) proteins. MATERIALS AND METHODS: We used immunohistochemistry to examine the distribution of Mcm-2 in breast tissue. Power calculations based on a pilot study of 67 whole tissue sections led to selection of an independent 347-core breast carcinoma tissue microarray validation set. We tested for associations between Mcm-2 (and Ki-67) labeling index (LI) and various clinicopathologic parameters. RESULTS: Mcm-2 was expressed more frequently than the standard proliferation marker Ki-67 in whole tissue sections of normal breast (P =.0003) and breast carcinoma (P <.0001). In 221 assessable cores of invasive carcinoma, the Mcm-2 LI showed a positive association with tumor size (P =.002), mitotic index (P <.0001), histologic grade (P <.0001), and the Nottingham Prognostic Index (NPI) score (P <.0001). Using a cutoff value of 50%, Mcm-2 LI was associated with overall survival (P =.0007), disease-free interval (P =.0002), and with the development of regional recurrence (P =.011) and distant metastases (P =.0016). Cox regression analysis suggested that the Mcm-2 LI is a strong prognostic factor in breast cancer that is independent and superior to histologic grade, lymph node stage, and Ki-67 LI, but not the NPI score. CONCLUSION: Mcm-2 may be of utility as a prognostic marker to refine the prediction of outcome in breast cancer, for example when combined with parameters currently used in the NPI.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Adulto , Idoso , Neoplasias da Mama/patologia , Replicação do DNA , Progressão da Doença , Feminino , Humanos , Técnicas Imunoenzimáticas , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Componente 2 do Complexo de Manutenção de Minicromossomo , Invasividade Neoplásica/diagnóstico , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Ductais, Lobulares e Medulares/diagnóstico , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neoplasias Ductais, Lobulares e Medulares/patologia , Projetos Piloto , Pré-Menopausa , Prognóstico
16.
Breast Cancer Res Treat ; 81(3): 195-207, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14620915

RESUMO

Tumor MUC1 expression as well as levels of MUC1, MUC1 circulating immune complexes (MUC1-CIC) and free antibodies against MUC1 (IgG and IgM-MUC1) were evaluated in 70 breast cancer patients with different stages of disease. Controls included: 135 serum samples from healthy women, normal mammary tissue samples (n = 7) and benign breast disease specimens (n = 6). In all assays, pre- and post-vaccination serum samples from breast cancer patients belonging to a vaccination protocol developed at the Memorial Sloan Kettering Cancer Center (New York, USA) were included as controls. Serum MUC1 was measured through Cancer Associated Serum Antigen test and CA15-3 test. Employing ELISA, MUC1-CIC-IgG/M were measured with either C595 or SM3 monoclonal antibodies (MAb) as catchers and also free antibodies against MUC1 (IgG and IgM) using 100mer peptide as catcher. Employing multivariate statistical analysis, results were correlated with age, tumor type, stage of disease and grade of differentiation. By quantitative immunohistochemistry using three anti-MUC1 core protein MAbs (C595, HMFG2 and SM3), tumor MUC1 was detected in 60/70 (86%) breast cancer specimens which reacted with at least one of these MAbs. High MUCI serum levels were detected in 14/67 (21%); IgG and IgM anti-MUC1 antibodies were found elevated in 32 and 14%, respectively, while IgG-MUC1-CIC-measured with C595 in 42% and IgM-MUC1-CIC in 54%; finally, SM3 was positive in 43 and 18%, respectively. Results of these studies demonstrate that in a group of breast cancer patients, MUC1 was detected both in tissue specimens as well as free in serum samples; furthermore, MUC1 can also circulate complexed with IgG and IgM antibodies; thus an accurate measurement should include free and complexed forms. On the other hand, immunohistochemical studies on breast cancer tissues may contribute to reveal different MUC1 glycoforms.


Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Mucina-1/metabolismo , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Adenocarcinoma/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo Antígeno-Anticorpo/imunologia , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/sangue , Feminino , Humanos , Imunoglobulina G/análise , Imunoglobulina M/análise , Pessoa de Meia-Idade , Mucina-1/sangue , Mucina-1/imunologia , Neoplasias Ductais, Lobulares e Medulares/sangue , Distribuição Tecidual
18.
Oncogene ; 21(36): 5619-30, 2002 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12165861

RESUMO

The three human TACC genes encode a family of proteins that are suspected to play a role in carcinogenesis. Their function is not precisely known; a Xenopus TACC protein called Maskin is involved in translational control, while the Drosophila D-TACC associates with microtubules and centrosomes. We have characterized the human TACC1 gene and its products. The TACC1 gene is located in region p12 of chromosome 8; its mRNA is ubiquitously expressed and encodes a protein with an apparent molecular mass of 125 kDa, which is cytoplasmic and mainly perinuclear. We show that TACC1 mRNA gene expression is down-regulated in various types of tumors. Using immunohistochemistry of tumor tissue-microarrays and sections, we confirm that the level of TACC1 protein is down-regulated in breast cancer. Finally, using the two-hybrid screen in yeast, GST pull-downs and co-immunoprecipitations, we identified two potential binding partners for TACC1, LSM7 and SmG. They constitute a conserved subfamily of Sm-like small proteins that associate with U6 snRNPs and play a role in several aspects of mRNA processing. We speculate that down-regulation of TACC1 may alter the control of mRNA homeostasis in polarized cells and participates in the oncogenic processes.


Assuntos
Neoplasias da Mama/genética , Proteínas Fetais , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Ductais, Lobulares e Medulares/genética , Proteínas Nucleares , RNA Mensageiro/metabolismo , Northern Blotting , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Primers do DNA/química , Regulação para Baixo , Feminino , Imunofluorescência , Glutationa Transferase/metabolismo , Humanos , Immunoblotting , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neoplasias Ductais, Lobulares e Medulares/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Fragmentos de Peptídeos/imunologia , Reação em Cadeia da Polimerase , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Saccharomyces cerevisiae , Frações Subcelulares , Células Tumorais Cultivadas/citologia , Técnicas do Sistema de Duplo-Híbrido
19.
Int J Oncol ; 20(4): 717-21, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11894115

RESUMO

Angiogenesis is intimately related to the growth and progression of tumours and must be induced to facilitate growth beyond a minimum size. It has been implicated in the development of metastases and survival in breast carcinoma. VEGF is a cytokine that plays an important role in angiogenesis. Its expression is increased in solid tumours during induction of angiogenesis and it has been implicated as a prognostic marker in patients with node negative breast carcinoma. We studied VEGF expression, in a series of patients with node positive breast carcinoma and examined histopathological parameters of the tumour and the prognostic value of VEGF expression. Specimens from 108 cases of node positive breast cancer were stained for VEGF using an antibody suitable for use on formalin fixed tissue. VEGF staining was cytoplasmic and was scored by intensity and the percent positive cells. Patients with positive VEGF staining (n=48) were compared with patients with negative VEGF staining (n=60). Demographic criteria were similar in both groups. Only one (12%) patient with lobular carcinoma and one (14%) patient with medullary carcinoma expressed VEGF compared with 46 (49%) patients with ductal carcinoma (NOS). DCIS was present in 60 tumours. There was a strong correlation between staining in DCIS and the adjacent invasive tumours. There was no significant association between VEGF staining and T stage, tumour size or the number of positive lymph nodes. VEGF expression had no prognostic significance either for disease-free or overall survival in patients with node positive disease. This study failed to support a role for VEGF as a prognostic marker in patients with node positive breast carcinoma.


Assuntos
Neoplasias da Mama/metabolismo , Fatores de Crescimento Endotelial/metabolismo , Linfocinas/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Intraductal não Infiltrante/terapia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Linfonodos/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Neoplasias Ductais, Lobulares e Medulares/patologia , Neoplasias Ductais, Lobulares e Medulares/terapia , Prognóstico , Receptores de Estrogênio/metabolismo , Taxa de Sobrevida , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
20.
Clin Cancer Res ; 8(3): 811-6, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11895913

RESUMO

PURPOSE: The purpose was to evaluate the utility of some bcl-2 family proteins fas and fasL as predictive indicators for chemotherapy response in advanced breast cancer. EXPERIMENTAL DESIGN: Between October 1994 and October 1997, 283 patients with advanced breast cancer were included in a multicenter randomized study comparing docetaxel (D) to sequential methotrexate and 5-fluorouracil (MF) after anthracycline failure. The response rates (complete response + partial response) were 42 and 21% in the D and MF arms, respectively (P < 0.001). In 126 patients, histological blocks of primary tumors were available for immunohistochemical analysis of bax, bcl-2, bcl-xL, bag-1, fas and fasL. RESULTS: Of the investigated factors, bag-1 correlated positively with bax, bcl-2, and fasL, and fasL correlated positively with fas and bax. None of these apoptosis-related factors was associated with a response to chemotherapy either in the whole patient population or in the D or MF arms. Interestingly, low bcl-2 expression was associated with shorter time to progression (P = 0.02) and shorter overall survival (OS; P = 0.001). High fasL expression showed a trend toward shorter OS. In multivariate backwards stepwise Cox analysis, in which histological grade and estrogen receptor status (ER) were also included, bcl-2 (P = 0.01) and fasL (P = 0.005) remained highly significantly associated with OS, whereas histological grade and ER lost their significance. CONCLUSIONS: None of the investigated apoptosis-related factors of primary tumor could predict the later response to either D or MF treatment. However, fasL and bcl-2 were strong prognostic factors. Patients who had tumors with high fasL and low bcl-2 expression had the shortest OS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Glicoproteínas de Membrana/metabolismo , Neoplasias Ductais, Lobulares e Medulares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor fas/metabolismo , Adolescente , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA , Resistencia a Medicamentos Antineoplásicos , Proteína Ligante Fas , Feminino , Fluoruracila/administração & dosagem , Humanos , Técnicas Imunoenzimáticas , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Neoplasias Ductais, Lobulares e Medulares/tratamento farmacológico , Neoplasias Ductais, Lobulares e Medulares/patologia , Prognóstico , Proteínas Proto-Oncogênicas/metabolismo , Taxa de Sobrevida , Fatores de Transcrição , Proteína X Associada a bcl-2 , Proteína bcl-X
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