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De Oliveira S.F.V.,Federal University of Parana | De Oliveira S.F.V.,University of South Santa Catarina | Ganzinelli M.,Laboratory of Molecular Pharmacology | Chila R.,Laboratory of Molecular Pharmacology | And 10 more authors.
PLoS ONE | Year: 2016

MTAP is a ubiquitously expressed gene important for adenine and methionine salvage. The gene is located at 9p21, a chromosome region often deleted in breast carcinomas, similar to CDKN2A, a recognized tumor suppressor gene. Several research groups have shown that MTAP acts as a tumor suppressor, and some therapeutic approaches were proposed based on a tumors̈ MTAP status. We analyzed MTAP and CDKN2A gene (RT-qPCR) and protein (western-blotting) expression in seven breast cancer cell lines and evaluated their promoter methylation patterns to better characterize the contribution of these genes to breast cancer. Cytotoxicity assays with inhibitors of de novo adenine synthesis (5-FU, AZA and MTX) after MTAP gene knockdown showed an increased sensitivity, mainly to 5-FU. MTAP expression was also evaluated in two groups of samples from breast cancer patients, fresh tumors and paired normal breast tissue, and from formalin-fixed paraffin embedded (FFPE) core breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors (TNBC). The difference of MTAP expression between fresh tumors and normal tissues was not statistically significant. However, MTAP expression was significantly higher in Luminal-A breast tumors than in TNBC, suggesting the lack of expression in more aggressive breast tumors and the possibility of using the new approaches based on MTAP status in TNBC. Copyright © 2016 Oliveira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source


Foroni C.,Laboratorio Of Oncologia Molecolare Senologica | Broggini M.,Laboratory of Molecular Pharmacology | Generali D.,Laboratorio Of Oncologia Molecolare Senologica | Damia G.,Laboratory of Molecular Pharmacology
Cancer Treatment Reviews | Year: 2012

Epithelial-mesenchymal transition (EMT) is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. In this process, cells acquire molecular alterations that facilitate dysfunctional cell-cell adhesive interactions and junctions. These processes may promote cancer cell progression and invasion into the surrounding microenvironment. Such transformation has implications in progression of breast carcinoma to metastasis, and increasing evidences support most tumors contain a subpopulation of cells with stem-like and mesenchymal features that is resistant to chemotherapy. This review focuses on the physiological and pathological role of EMT process, its molecular related network, its putative role in the metastatic process and its implications in response/resistance to the current and/or new approaching drugs in the clinical management of breast cancer. © 2011 Elsevier Ltd. Source


Allevi G.,Laboratorio Of Oncologia Molecolare Senologica | Strina C.,Laboratorio Of Oncologia Molecolare Senologica | Andreis D.,Laboratorio Of Oncologia Molecolare Senologica | Zanoni V.,Laboratorio Of Oncologia Molecolare Senologica | And 15 more authors.
British Journal of Cancer | Year: 2013

Background: The objective of this study was to determine the optimal scheduling of 2.5 mg daily letrozole in neoadjuvant breast cancer patients to obtain pathological complete response (pathCR) and assess Ki-67 expression as an early predictor of response.Patients and methods:This single institution study comprised 120 oestrogen receptor (ER)-positive postmenopausal women with primary breast cancer (clinical stage ≥T2, N0-1), from three sequential cohorts (cohort A of 40, cohort B of 40 and cohort C of 40 patients, respectively) based on different duration of the neoadjuvant letrozole. Biological markers such as ER, progesterone receptor, HER2 and Ki-67 expression were tested at diagnosis and at definitive surgery.Results:A total of 89 patients (75.4%) achieved an objective response with 44 (37.3%) clinical CRs and 45 (38.1%) partial responses. The clinical CRs were significantly observed in cohort C (23 out of 40 patients, 57.5%) and B (16 out of 38 patients, 42.1%) compared with cohort A (5 out of 40 patients, 12.5%) (P-value for trend <0.001). Letrozole induced a similar significant reduction in Ki-67 index after treatment in all cohorts. The pathCR rate was significantly more frequent in cohort C (7 out of 40 patients, 17.5%) than in cohort A (1 out of 40 patients, 2.5%) and B (2 out of 40 patients, 5.0%) (P-value for trend <0.04).Conclusion:One-year neoadjuvant letrozole therapy leads to a higher pathCR rate and may be the optimal length of drug exposure. © 2013 Cancer Research UK. All rights reserved. Source


Ribeiro E.,Federal University of Parana | Ganzinelli M.,Laboratory of Molecular Pharmacology | Andreis D.,Laboratorio Of Oncologia Molecolare Senologica | Bertoni R.,UOAnatomia Patologica | And 9 more authors.
PLoS ONE | Year: 2013

DNA repair is a key determinant in the cellular response to therapy and tumor repair status could play an important role in tailoring patient therapy. Our goal was to evaluate the mRNA of 13 genes involved in different DNA repair pathways (base excision, nucleotide excision, homologous recombination, and Fanconi anemia) in paraffin embedded samples of triple negative breast cancer (TNBC) compared to luminal A breast cancer (LABC). Most of the genes involved in nucleotide excision repair and Fanconi Anemia pathways, and CHK1 gene were significantly less expressed in TNBC than in LABC. PARP1 levels were higher in TNBC than in LABC. In univariate analysis high level of FANCA correlated with an increased overall survival and event free survival in TNBC; however multivariate analyses using Cox regression did not confirm FANCA as independent prognostic factor. These data support the evidence that TNBCs compared to LABCs harbour DNA repair defects. © 2013 Ribeiro et al. Source

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