RESUMO
In order to better understand the process of breast cancer metastasis, we have generated a mammary epithelial progression series of increasingly aggressive cell lines that metastasize to lung. Here we demonstrate that upregulation of an endoplasmic reticulum (ER) to Golgi trafficking gene signature in metastatic cells enhances transport kinetics, which promotes malignant progression. We observe increased ER-Golgi trafficking, an altered secretome and sensitivity to the retrograde transport inhibitor brefeldin A (BFA) in cells that metastasize to lung. CREB3 was identified as a transcriptional regulator of upregulated ER-Golgi trafficking genes ARF4, COPB1, and USO1, and silencing of these genes attenuated the metastatic phenotype in vitro and lung colonization in vivo. Furthermore, high trafficking gene expression significantly correlated with increased risk of distant metastasis and reduced relapse-free and overall survival in breast cancer patients, suggesting that modulation of ER-Golgi trafficking plays an important role in metastatic progression.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Animais , Neoplasias da Mama/mortalidade , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Análise em Microsséries , Metástase Neoplásica , Transporte Proteico/genética , Transcriptoma/genética , Células Tumorais CultivadasRESUMO
Breast cancer (BC) has a higher incidence in young Lebanese woman as compared to the West. We assessed the microRNA (miRNA) microarray profile of tissues derived from Lebanese patients with early BC and performed mRNA-miRNA integration analysis. 173 miRNAs were significantly dysregulated in 45 BC versus 17 normal adjacent breast tissues, including 74 with a fold change more than two of which 17 were never reported before in cancer. Integration analysis of mRNA-miRNA microarray data revealed a potential role of 51 dysregulated miRNA regulating 719 tumor suppressive or oncogenic mRNA associated with increased proliferation and decreased migration and invasion. We then performed a comparative miRNA microarray profile analysis of BC tissue between these 45 Lebanese and 197 matched American BC patients. Notably, Lebanese BC patients had 21 exclusively dysregulated miRNA (e.g. miR-31, 362-3p, and 663) and 4 miRNA with different expression manner compared to American patients (e.g. miR-1288-star and 324-3p). Some of these differences could reflect variation in patient age at diagnosis or ethnic variation affecting miRNA epigenetic regulation or sequence of miRNA precursors. Our data provide a basis for genetic/epigenetic investigations to explore the role of miRNA in early stage BC in young women, including ethnic specific differences.
Assuntos
Neoplasias da Mama/patologia , MicroRNAs/metabolismo , Adulto , Neoplasias da Mama/etnologia , Neoplasias da Mama/genética , Carcinoma Ductal/etnologia , Carcinoma Ductal/genética , Carcinoma Ductal/patologia , Movimento Celular , Proliferação de Células , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Líbano , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/metabolismo , Transcriptoma , Células Tumorais Cultivadas , Estados UnidosRESUMO
Relative to western populations, the percentage of women diagnosed with breast cancer at a young age in Lebanon is high. While the younger age of the Lebanese population compared to the West certainly contributes to this difference, potential genetic, reproductive and/or biological factors likely play an important role. The objective of this study is to investigate the contribution of miRNAs in this setting through the analysis of the expression of five reported dysregulated miRNAs, miR-148b, miR-10b, miR-21, miR-221, and miR-155 in 20 normal and 57 cancerous breast tissues from Lebanese breast cancer patients. After finding their relative expression by quantitative reverse transcription real time PCR, the results were analyzed with respect to the patients' clinical and histopathology presentations. Compared to normal breast tissues, significant upregulation of miR-155, miR-21 and miR-148b, notable downregulation of miR-10b and non-significant expression of miR-221 were observed in tumor tissues. Moreover, miR-10b was significantly underexpressed in estrogen/progesterone receptor (ER/PR) negative tumors relative to ER/PR positive tumor tissues. miR-155 was also significantly overexpressed in postmenopausal patients and in those of age at diagnosis greater than 40 years old as well as in PR negative or in human epidermal growth factor 2 (Her2) positive tissues. This study is the first one to report miRNA expression patterns in Lebanese breast cancer patients. We found that differential miRNA expression in breast cancer could be variable between Lebanese and Western populations. miR-10b was positively correlated with the ER and PR status and miR-155 could be a noteworthy biomarker for the menopausal state, age at diagnosis, PR and Her2 status. Hence, miRNA can be used as biomarkers for early breast cancer detection.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , MicroRNAs/genética , Adulto , Mama/patologia , Neoplasias da Mama/epidemiologia , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Marcadores Genéticos/genética , Humanos , Líbano/epidemiologia , MicroRNAs/biossíntese , Projetos Piloto , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para CimaRESUMO
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI) therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML) that have the potential to target CML stem cells and potentially provide cure for CML.