RESUMO
Plasma and tissue from breast cancer patients are valuable for diagnostic/prognostic purposes and are accessible by multiple mass spectrometry (MS) tools. Liquid chromatography-mass spectrometry (LC-MS) and ambient mass spectrometry imaging (MSI) were shown to be robust and reproducible technologies for breast cancer diagnosis. Here, we investigated whether there is a correspondence between lipid cancer features observed by desorption electrospray ionization (DESI)-MSI in tissue and those detected by LC-MS in plasma samples. The study included 28 tissues and 20 plasma samples from 24 women with ductal breast carcinomas of both special and no special type (NST) along with 22 plasma samples from healthy women. The comparison of plasma and tissue lipid signatures revealed that each one of the studied matrices (i.e., blood or tumor) has its own specific molecular signature and the full interposition of their discriminant ions is not possible. This comparison also revealed that the molecular indicators of tissue injury, characteristic of the breast cancer tissue profile obtained by DESI-MSI, do not persist as cancer discriminators in peripheral blood even though some of them could be found in plasma samples.
Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal/metabolismo , Metabolismo dos Lipídeos , Lipidômica/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Carcinoma Ductal/sangue , Feminino , Humanos , Lipídeos/sangue , Pessoa de Meia-IdadeRESUMO
Breast cancer is a group of multigenic diseases. It is the most common cancer diagnosed among women worldwide and is often treated with tamoxifen. Tamoxifen is catalysed by cytochrome P450 2D6 (CYP2D6), and inter-individual variations in the enzyme due to single nucleotide polymorphisms (SNPs) could alter enzyme activity. We evaluated SNPs in patients from Colombia in South America who were receiving tamoxifen treatment for breast cancer. Allelic diversity in the CYP2D6 gene was found in the studied population, with two patients displaying the poor-metaboliser phenotype. Molecular dynamics and trajectory analyses were performed for CYP2D6 from these two patients, comparing it with the common allelic form (CYP2D6*1). Although we found no significant structural change in the protein, its dynamics differ significantly from those of CYP2D6*1, the effect of such differential dynamics resulting in an inefficient enzyme with serious implications for tamoxifen-treated patients, increasing the risk of disease relapse and ineffective treatment.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal/tratamento farmacológico , Citocromo P-450 CYP2D6/genética , Tamoxifeno/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal/genética , Carcinoma Ductal/metabolismo , Carcinoma Ductal/patologia , Quimioterapia Adjuvante , Citocromo P-450 CYP2D6/metabolismo , Feminino , Genótipo , Humanos , Inativação Metabólica/genética , Pessoa de Meia-Idade , Variantes Farmacogenômicos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Tamoxifeno/efeitos adversos , Tamoxifeno/metabolismoRESUMO
Salivary gland cancers represent a rare group of tumors composed by over 20 histological subtypes. Initially treated as one single disease, its diagnosis, prognosis, and treatment are currently being stratified based on morphology. More recently, insight has been provided on the molecular characterization of each subtype, further improving diagnostic accuracy and paving the way for personalized therapy. In this article, we provide a comprehensive review of recent breakthroughs, preliminary results of novel therapy, and future directions on the treatment of these complex malignancies.
Assuntos
Neoplasias das Glândulas Salivares , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Adenoide Cístico/genética , Carcinoma Adenoide Cístico/metabolismo , Carcinoma Adenoide Cístico/terapia , Carcinoma Ductal/genética , Carcinoma Ductal/metabolismo , Carcinoma Ductal/terapia , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/metabolismo , Carcinoma Mucoepidermoide/terapia , Análise Mutacional de DNA , Perfilação da Expressão Gênica , Humanos , Mutação , Ductos Salivares/patologia , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/terapiaRESUMO
The aim of the study was to assess the relationship between the expression of COX-2 and p53, hormone receptors and HER-2 in the in situ (DCIS) and invasive components of ductal carcinomas (IDC) of the same breast. The expression of COX-2, p53, and hormone receptors was assessed in 87 cases of IDC with contiguous areas of DCIS. Results showed that there was no difference in COX-2 expression comparing the in situ and invasive components of the tumors. In the in situ component, there was a statistically borderline increase in p53 expression in tumors that also expressed COX-2. ER-positive specimens were more common in the group of tumors that expressed COX-2 in the invasive component. From this study we conclude that the expression of COX-2 was similar in the in situ and invasive components of the breast carcinomas. COX-2 positivity was marginally related with the expression of p53 in the in situ components, and with the ER expression in the invasive components.
Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Carcinoma Ductal/patologia , Ciclo-Oxigenase 2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal/genética , Carcinoma Ductal/metabolismo , Ciclo-Oxigenase 2/genética , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Invasividade Neoplásica , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Microambiente Tumoral , Proteína Supressora de Tumor p53/genéticaRESUMO
Breast cancer is a complex and heterogeneous disease. In spite of the advances made in recent decades, a better understanding of the intrinsic mechanisms of this disease is crucial. The development of new biomarkers is absolutely necessary to improve diagnosis and prognosis. Research using the proteomic approach has generated interesting results; however, the complexity of the mammary gland and of breast tumors remains a major limitation to the development of new markers. An initial step is to characterize non-tumoral human breast tissue. We present data from classical proteomic analysis based on 2-D electrophoresis and peptide mass fingerprinting identification, which were performed on six non-tumoral samples from patients with invasive ductal breast carcinomas. Forty-four different proteins from 70 spots were identified and classified according to their biological function. Cytoskeleton and associated proteins represent the largest class (30%) followed by the proteins with binding function (27%). Several of the proteins have been described in breast tumors, such as vimentin, endoplasmin, small heat shock beta-6, disulfide isomerase and some cell growth, and proliferation regulators, suggesting the importance of including data on the characterization of non-tumoral breast and to studies on differential expression in cancer tissue.
Assuntos
Glândulas Mamárias Humanas/metabolismo , Proteoma/metabolismo , Proteômica , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal/diagnóstico , Carcinoma Ductal/metabolismo , Carcinoma Ductal/patologia , Feminino , Humanos , Glândulas Mamárias Humanas/patologia , Pessoa de Meia-Idade , PrognósticoRESUMO
More than 60% of all breast neoplasias are ductal carcinomas expressing estrogen (ER) and progesterone receptors (PR). By contrast, most of the spontaneous, chemically or mouse mammary tumor virus induced tumors, as well as tumors arising in genetically modified mice do not express hormone receptors. We developed a model of breast cancer in which the administration of medroxyprogesterone acetate to BALB/c female mice induces mammary ductal carcinomas with a mean latency of 52 weeks and an incidence of about 80%. These tumors are hormone-dependent (HD), metastatic, express both ER and PR, and are maintained by syngeneic transplants. The model has been further refined to include mammary carcinomas that evolve through different stages of hormone dependence, as well as several hormone-responsive cell lines. In this review, we describe the main features of this tumor model, highlighting the role of PR as a trigger of key signaling pathways mediating tumor growth. In addition, we discuss the relevance of this model in comparison with other presently used breast cancer models pointing out its advantages and limitations and how, this model may be suitable to unravel key questions in breast cancer.
Assuntos
Carcinoma Ductal/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Hormônio-Dependentes/metabolismo , Receptores de Progesterona/fisiologia , Animais , Antineoplásicos Hormonais/toxicidade , Feminino , Neoplasias Mamárias Experimentais/patologia , Acetato de Medroxiprogesterona/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Estrogênio/metabolismoRESUMO
Success in breast cancer treatment depends greatly upon early detection, and in the employment of prognostic markers able to anticipate the evolution of the disease, allowing a more rational management of the patient. A fundamental cause of cancer is the alteration of the genetic material, which may modify the expression of proteins that play key roles in cell cycle progression. The aim of this study was to analyze the expression of cyclins D1, E, and B1 and of the CDKIs p16 and p21 in a population of uniformly treated patients with stage I or II breast tumors (n=56) compared with patients with benign breast pathology (n=23). Malignant breast tumors showed higher cyclin E and lower p21 expression than benign breast pathology (NS), determined by immunohistochemistry (IHC). In breast cancer patients, overexpression of cyclins D1 and E was associated with the presence of ER and stage respectively independently of other prognostic variables (multivariate analysis). Kaplan-Meier curves demonstrated that only overexpression of cyclin E was associated with a longer recurrence-free survival. Cox analysis showed that neither cyclins nor CDKIs were independent prognostic markers. We demonstrated that several regulators of cell cycle progression were altered in a large number of breast tumor cases, however, these abnormalities were not indicators of a worse outcome in breast cancer patients of stages I and II.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Ciclo Celular , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Neoplasias da Mama/cirurgia , Carcinoma Ductal/diagnóstico , Carcinoma Ductal/metabolismo , Carcinoma Ductal/cirurgia , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/cirurgia , Proteínas de Ciclo Celular/análise , Proteínas de Ciclo Celular/metabolismo , Ciclina B/metabolismo , Ciclina B1 , Ciclina D1/metabolismo , Ciclina E/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21 , Inibidor de Quinase Dependente de Ciclina p27 , Feminino , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Proteínas Supressoras de TumorRESUMO
Urokinase plasminogen activator (uPA), its cell-bound receptor (uPAR) and its main inhibitor plasminogen activator type 1 (PAI-1) are present primarily in stromal cells in invasive breast carcinoma. The purpose of this study was to investigate the regulation by 1,25 dihydroxyvitamin-D3 (VD3) of these invasion-associated markers expressed in breast cancer tumors under organ culture, which preserves the interacting network of tumor and stromal cells. Breast carcinoma slices (30 cases), obtained using the Krumdieck tissue slicer, cultured for 48 h in the presence or absence of 100 nM vitamin D3, were embedded in formalin-fixed paraffin. uPA, uPAR, PAI-1 and VD3 receptor (VDR) were analyzed by immunohistochemistry, and their expression, detected in tumor cells and fibroblasts of the specimens, was not statistically changed by culture conditions. The proportion of cases expressing uPA, uPAR and PAI-1 was not affected by VD3 in epithelial cells, but the fraction of cases displaying strong PAI-1 reactivity in fibroblasts was reduced ( P=0.016) compared with control slices. Fibroblasts isolated from invasive ductal carcinomas and from normal breast tissues expressed higher VDR mRNA levels than epithelial cells. In cultured tumor fibroblasts, PAI-1 immunostaining and mRNA levels were reduced by VD3-limiting fibroblast contribution to invasion.