MARIA APARECIDA NAGAI
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Radiologia, Faculdade de Medicina - Docente
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
8 resultados
Resultados de Busca
Agora exibindo 1 - 8 de 8
- Abnormal Long Non-Coding RNAs Expression Patterns Have the Potential Ability for Predicting Survival and Treatment Response in Breast Cancer(2021) PAVANELLI, Ana Carolina; MANGONE, Flavia Rotea; BARROS, Luciana R. C.; MACHADO-RUGOLO, Juliana; CAPELOZZI, Vera L.; NAGAI, Maria A.Abnormal long non-coding RNAs (lncRNAs) expression has been documented to have oncogene or tumor suppressor functions in the development and progression of cancer, emerging as promising independent biomarkers for molecular cancer stratification and patients' prognosis. Examining the relationship between lncRNAs and the survival rates in malignancies creates new scenarios for precision medicine and targeted therapy. Breast cancer (BRCA) is a heterogeneous malignancy. Despite advances in its molecular classification, there are still gaps to explain in its multifaceted presentations and a substantial lack of biomarkers that can better predict patients' prognosis in response to different therapeutic strategies. Here, we performed a re-analysis of gene expression data generated using cDNA microarrays in a previous study of our group, aiming to identify differentially expressed lncRNAs (DELncRNAs) with a potential predictive value for response to treatment with taxanes in breast cancer patients. Results revealed 157 DELncRNAs (90 up- and 67 down-regulated). We validated these new biomarkers as having prognostic and predictive value for breast cancer using in silico analysis in public databases. Data from TCGA showed that compared to normal tissue, MIAT was up-regulated, while KCNQ1OT1, LOC100270804, and FLJ10038 were down-regulated in breast tumor tissues. KCNQ1OT1, LOC100270804, and FLJ10038 median levels were found to be significantly higher in the luminal subtype. The ROC plotter platform results showed that reduced expression of these three DElncRNAs was associated with breast cancer patients who did not respond to taxane treatment. Kaplan-Meier survival analysis revealed that a lower expression of the selected lncRNAs was significantly associated with worse relapse-free survival (RFS) in breast cancer patients. Further validation of the expression of these DELncRNAs might be helpful to better tailor breast cancer prognosis and treatment.
- Prognostic and predictive value of Pleckstrin homology-like domain, family A family members in breast cancer(2020) MANGONE, Flavia R.; VALOYES, Maira A. V.; NASCIMENTO, Renan G. do; CONCEICAO, Mercia P. F.; BASTOS, Daniel R.; PAVANELLI, Ana C.; SOARES, Ibere C.; MELLO, Evandro S. de; NONOGAKI, Suely; OSORIO, Cynthia A. B.; NAGAI, Maria A.Aim: The PHLDA (pleckstrin homology like domain, family A) gene family encodes proteins capable of inhibiting AKT (serine/threonine kinase) signaling through phosphoinositol binding competition. Results & methodology: Using in silico analysis, we found that Luminal A and B patients' short relapse-free survival was associated with low PHLDA1 or PHLDA3 and high PHLDA2 expression. In a cohort of 393 patients with luminal breast cancer evaluated by immunohistochemistry on tissue microarrays, we found a direct association of PHLDA3 expression with hormonal therapy response (p = 0.013). Conclusion: Our findings provide new information on the role played by the PHLDA family members as prognostic markers in breast cancer, and more importantly, we provide evidence that they might also predict a response to endocrine therapy.
- Prostate apoptosis response-4 is involved in the apoptosis response to docetaxel in MCF-7 breast cancer cells(2013) PEREIRA, Michelly C.; BESSA-GARCIA, Simone A. De; BURIKHANOV, Ravshan; PAVANELLI, Ana Carolina; ANTUNES, Lourival; RANGNEKAR, Vivek M.; NAGAI, Maria A.Experimental evidence indicates that prostate apoptosis response-4 (Par-4, also known as PAWR) is a key regulator of cancer cell survival and may be a target for cancer-selective targeted therapeutics. Par-4 was first identified in prostate cancer cells undergoing apoptosis. Both intracellular and extracellular Par-4 have been implicated in apoptosis. Relatively little is known about the role of Par-4 in breast cancer cell apoptosis. In this study, we sought to investigate the effects of Par-4 expression on cell proliferation, apoptosis and drug sensitivity in breast cancer cells. MCF-7 cells were stably transfected with expression vectors for Par-4, or transiently transfected with siRNA for Par-4 knockdown. Cell proliferation assays were performed using MTT and apoptosis was evaluated using acridine orange staining, fluorescence microscopy and flow cytometry. Par-4 overexpression reduced MCF-7 proliferation rates. Conversely, Par-4 knockdown led to increased MCF-7 proliferation. Par-4 downregulation also led to increased BCL-2 and reduced BID expression. Par-4 overexpression did not affect the cell cycle profile. However, MCF-7 cells with increased Par-4 expression showed reduced ERK phosphorylation, suggesting that the inhibition of cell proliferation promoted by Par-4 may be mediated by the MAPK/ERK1/2 pathway. MCF-7 cells with increased Par-4 expression showed a marginal increase in early apoptotic cells. Importantly, we found that Par-4 expression modulates apoptosis in response to docetaxel in MCF7 breast cancer cells. Par-4 exerts growth inhibitory effects on breast cancer cells and chemosensitizes them to docetaxel.
- Socioeconomic, Clinical, and Molecular Features of Breast Cancer Influence Overall Survival of Latin American Women(2022) ALMEIDA, Liz Maria de; CORTES, Sandra; VILENSKY, Marta; VALENZUELA, Olivia; CORTES-SANABRIA, Laura; SOUZA, Mirian de; BARBEITO, Rafael Alonso; ABDELHAY, Eliana; ARTAGAVEYTIA, Nora; DANERI-NAVARRO, Adrian; LLERA, Andrea S.; MULLER, Bettina; PODHAJCER, Osvaldo L.; VELAZQUEZ, Carlos; ALCOBA, Elsa; ALONSO, Isabel; I, Alicia Bravo; CAMEJO, Natalia; CARRARO, Dirce Maria; CASTRO, Monica; CATALDI, Sandra; CAYOTA, Alfonso; CERDA, Mauricio; COLOMBO, Alicia; CROCAMO, Susanne; TORO-ARREOLA, Alicia Del; DELGADILLO-CRISTERNA, Raul; DELGADO, Lucia; BREITENBACH, Marisa Dreyer; FERNANDEZ, Elmer; FERNANDEZ, Jorge; FERNANDEZ, Wanda; FRANCO-TOPETE, Ramon A.; GAETE, Fancy; GOMEZ, Jorge; GONZALEZ-RAMIREZ, Leivy P.; GUERRERO, Marisol; GUTIERREZ-RUBIO, Susan A.; JALFIN, Beatriz; LOPEZ-VAZQUEZ, Alejandra; LORIA, Dora; MIGUEZ, Silvia; MORAN-MENDOZA, Andres de J.; MORGAN-VILLELA, Gilberto; MUSSETTI, Carina; NAGAI, Maria Aparecida; OCEGUERA-VILLANUEVA, Antonio; REIS, Rui M.; RETAMALES, Javier; RODRIGUEZ, Robinson; ROSALES, Cristina; SALAS-GONZALEZ, Efrain; SEGOVIA, Laura; SENDOYA, Juan M.; SILVA-GARCIA, Aida A.; VINA, Stella; ZAGAME, Livia; JONES, Beth; SZKLO, MoysesMolecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status not less than or equal to 1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher's exact tests and the OS by Kaplan-Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (>= 60 years) (1.84) compared with younger (<= 40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.
- Insulin-like growth factor-1 and 17 beta-estradiol down-regulate prostate apoptosis response-4 expression in MCF-7 breast cancer cells(2011) CASOLARI, Debora A.; PEREIRA, Michelly C.; GARCIA, Simone A. De Bessa; NAGAI, Maria A.The PKC apoptosis WTI regulator gene, also named prostate apoptosis response-4 (PAR-4), encodes a pro-apoptotic protein that sensitizes cells to numerous apoptotic stimuli. Insulin-like growth factor-1 (IGF-1) and 17 beta-estradiol (E2), two important factors for breast cancer development and progression, have been shown to down-regulate PAR-4 expression and inhibit apoptosis induced by PAR-4 in neuronal cells. In this study, we sought to investigate the mechanisms of regulation of PAR-4 gene expression in MCF-7 cells treated with E2 or IGF-1. E2 (10 nM) and IGF-1 (12.5 nM) each down-regulated PAR-4 expression in MCF-7 cells after 24 h of treatment. The effect of E2 was dependent on ER activation, as demonstrated by an increase in PAR-4 expression when cells were pretreated for 1 h with 1 mu M ICI-182,780 (ICI) before receiving E2 plus ICI. The effect of IGF-1 was abolished by pre-treatment for 1 h with 30 mu M LY294002 (a specific PI3-K inhibitor), and significantly inhibited by 30 mu M SB202190 (a specific p38MAPK inhibitor). We also demonstrated that E2 acts synergistically with IGF-1, resulting in greater down-regulation of PAR-4 mRNA expression compared with E2 or IGF-1 alone. Our results show for the first time that E2 and IGF-1 inhibit PAR-4 gene expression in MCF-7 cells, suggesting that this down-regulation may provide a selective advantage for breast cancer cell survival.
- PHLDA1 (pleckstrin homology-like domain, family A, member 1) knockdown promotes migration and invasion of MCF10A breast epithelial cells(2018) BONATTO, Naieli; CARLINI, Maria Jose; GARCIA, Simone Aparecida de Bessa; NAGAI, Maria AparecidaPHLDA1 (pleckstrin homology-like domain, family A, member 1) is a multifunctional protein that plays distinct roles in several biological processes including cell death and therefore its altered expression has been identified in different types of cancer. Progressively loss of PHLDA1 was found in primary and metastatic melanoma while its overexpression was reported in intestinal and pancreatic tumors. Previous work from our group showed that negative expression of PHLDA1 protein was a strong predictor of poor prognosis for breast cancer disease. However, the function of PHLDA1 in mammary epithelial cells and the tumorigenic process of the breast is unclear. To dissect PHLDA1 role in human breast epithelial cells, we generated a clone of MCF10A cells with stable knockdown of PHLDA1 and performed functional studies. To achieve reduced PHLDA1 expression we used shRNA plasmid transfection and then changes in cell morphology and biological behavior were assessed. We found that PHLDA1 downregulation induced marked morphological alterations in MCF10A cells, such as changes in cell-to-cell adhesion pattern and cytoskeleton reorganization. Regarding cell behavior, MCF10A cells with reduced expression of PHLDA1 showed higher proliferative rate and migration ability in comparison with control cells. We also found that MCF10A cells with PHLDA1 knockdown acquired invasive properties, as evaluated by transwell Matrigel invasion assay and showed enhanced colony-forming ability and irregular growth in low attachment condition. Altogether, our results indicate that PHLDA1 downregulation in MCF10A cells leads to morphological changes and a more aggressive behavior.
- The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients(2022) LLERA, Andrea Sabina; ABDELHAY, Eliana Saul Furquim Werneck; ARTAGAVEYTIA, Nora; DANERI-NAVARRO, Adrian; MULLER, Bettina; VELAZQUEZ, Carlos; ALCOBA, Elsa B.; ALONSO, Isabel; QUINTA, Daniela B. Alves da; BINATO, Renata; BRAVO, Alicia Ines; CAMEJO, Natalia; CARRARO, Dirce Maria; CASTRO, Monica; CASTRO-CERVANTES, Juan M.; CATALDI, Sandra; CAYOTA, Alfonso; CERDA, Mauricio; COLOMBO, Alicia; CROCAMO, Susanne; TORO-ARREOLA, Alicia Del; DELGADILLO-CISTERNA, Raul; DELGADO, Lucia; DREYER-BREITENBACH, Marisa; FEJERMAN, Laura; FERNANDEZ, Elmer A.; FERNANDEZ, Jorge; FERNANDEZ, Wanda; FRANCO-TOPETE, Ramon A.; GABAY, Carolina; GAETE, Fancy; GARIBAY-ESCOBAR, Adriana; GOMEZ, Jorge; GREIF, Gonzalo; GROSS, Thomas G.; GUERRERO, Marisol; HENDERSON, Marianne K.; LOPEZ-MUNOZ, Miguel E.; LOPEZ-VAZQUEZ, Alejandra; MALDONADO, Silvina; MORAN-MENDOZA, Andres J.; NAGAI, Maria Aparecida; OCEGUERA-VILLANUEVA, Antonio; ORTIZ-MARTINEZ, Miguel A.; QUINTERO, Jael; QUINTERO-RAMOS, Antonio; REIS, Rui M.; RETAMALES, Javier; RIVERA-CLAISSE, Ernesto; ROCHA, Dario; RODRIGUEZ, Robinson; ROSALES, Cristina; SALAS-GONZALEZ, Efrain; SANCHOTENA, Veronica; SEGOVIA, Laura; SENDOYA, Juan Martin; SILVA-GARCIA, Aida A.; TRINCHERO, Alejandra; VALENZUELA, Olivia; VEDHAM, Vidya; ZAGAME, Livia; PODHAJCER, Osvaldo L.PurposesMost molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches. Patients and MethodsWe collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes. ResultsPAM50 classification of the MPBCS cohort defined 42 center dot 6% of tumors as LumA, 21 center dot 3% as LumB, 13 center dot 3% as HER2E and 16 center dot 6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors. ConclusionsThis is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America.
- Prostate apoptosis response 4 (PAR4) expression modulates WNT signaling pathways in MCF7 breast cancer cells: A possible mechanism underlying PAR4-mediated docetaxel chemosensitivity(2017) GARCIA, Simone Aparecida de Bessa; PAVANELLI, Ana Carolina; MELO, Natalia Cruz e; NAGAI, Maria AparecidaDocetaxel is an effective drug for the treatment of metastatic breast cancer. However, the exact mechanisms and/or markers associated with chemosensitivity or resistance to docetaxel remain unclear. We previously showed that the expression of prostate apoptosis response 4 (PAR4) inhibits the growth of MCF7 breast cancer cells and increases their sensitivity to docetaxel. Using cDNA microarray analysis, we evaluated transcriptome changes in MCF7 cells expressing increased levels of PAR4 and control cells before and after docetaxel treatment. Some of the top gene networks generated from the differentially expressed genes were related to the wingless-type MMTV integration 1 (WNT) canonical (WNT/-catenin) and non-canonical (-catenin-independent) pathways. The Human WNT signaling pathway RT2 profiler PCR array was used to validate the effects of PAR4 on the expression pattern of genes involved in the WNT pathway. CACNAD2A3, GDF5 and IL6 were upregulated and NANOG was downregulated in the MCF7 breast cancer cells expressing increased levels of PAR4 after treatment with docetaxel, likely indicating inactivation of the WNT/-catenin pathway. Upregulation of FGF7, LEF1 and TWIST1 indicated activation of the WNT/-catenin pathway. Although preliminary, our findings could be of particular interest for understanding the action of PAR4 in chemosensitivity, particularly to increase the specificity and effectiveness of drug treatment and overcome resistance to chemotherapy. Further studies are needed to better understand the biological roles of PAR4 in the regulation of WNT pathways in breast cancer cells in response to docetaxel and other chemotherapeutic agents.