FLAVIA REGINA ROTEA MANGONE
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina
11 resultados
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conferenceObject Transcriptome profiling of MCF7 cells with different expression pattern of SPARC (secreted protein acidic in rich in cysteine) in the presence and absence of Docetaxel(2013) PAVANELLI, Ana Carolina; MANGONE, Flavia R. R.; NAGAI, Maria Aparecida- Comprehensive immunohistochemical analysis of RET, BCAR1, and BCAR3 expression in patients with Luminal A and B breast cancer subtypes(2022) PAVANELLI, Ana Carolina; MANGONE, Flavia Rotea; YOGANATHAN, Piriya; BESSA, Simone Aparecida; NONOGAKI, Suely; OSORIO, Cynthia A. B. de Toledo; ANDRADE, Victor Piana de; SOARES, Ibere Cauduro; MELLO, Evandro Sobrosa de; MULLIGAN, Lois M.; NAGAI, Maria AparecidaPurpose Breast cancer (BC) is considered a heterogeneous disease composed of distinct subtypes with diverse clinical outcomes. Luminal subtype tumors have the best prognosis, and patients benefit from endocrine therapy. However, resistance to endocrine therapies in BC is an obstacle to successful treatment, and novel biomarkers are needed to understand and overcome this mechanism. The RET, BCAR1, and BCAR3 genes may be associated with BC progression and endocrine resistance. Methods Aiming to evaluate the expression profile and prognostic value of RET, BCAR1, and BCAR3, we performed immunohistochemistry on tissue microarrays (TMAs) containing a cohort of 361 Luminal subtype BC. Results Low expression levels of these three proteins were predominantly observed. BCAR1 expression was correlated with nuclear grade (p = 0.057), and BCAR3 expression was correlated with lymph node status (p = 0.011) and response to hormonal therapy (p = 0.021). Further, low expression of either BCAR1 or BCAR3 was significantly associated with poor prognosis (p = 0.005; p = 0.042). Pairwise analysis showed that patients with tumors with low BCAR1/low BCAR3 expression had a poorer overall survival (p = 0.013), and the low BCAR3 expression had the worst prognosis with RET high expression stratifying these patients into two different groups. Regarding the response to hormonal therapy, non-responder patients presented lower expression of RET in comparison to the responder group (p = 0.035). Additionally, the low BCAR1 expression patients had poorer outcomes than BCAR1 high (p = 0.015). Conclusion Our findings suggest RET, BCAR1, and BCAR3 as potential candidate markers for endocrine therapy resistance in Luminal BC.
- 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.
- Gene expression profiling of triple-negative breast tumors with different expression of secreted protein acidic and cysteine rich (SPARC)(2018) ALCANTARA FILHO, Paulo R. de; MANGONE, Flavia R.; PAVANELLI, Ana C.; GARCIA, Simone A. de Bessa; NONOGAKI, Suely; OSORIO, Cynthia A. B. de Toledo; ANDRADE, Victor P. de; NAGAI, Maria A.Aim: To determine the expression signature of triple-negative breast cancer (TNBC) with differences of secreted protein acidic and rich in cysteine expression and clinical behavior. Patients, materials & methods: cDNA microarray analysis was performed to determine the expression profiling of TNBC, characterized regarding secreted protein acidic and rich in cysteine expression status. Immunohistochemistry analysis on tissue microarrays containing an independent cohort of TNBC was performed for validation. Results: Negative staining of SOHLH2 and positive staining of DNAJC12 and LIM1 was correlated with a poor outcome of the patients. Conclusion: Our findings provide new information on transcriptome changes associated with the clinical behavior of TNBC that may serve as a potential tool for the identification and characterization of new candidate biomarkers.
- 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.
- Oxytocin Receptor Exon III Methylation in the Umbilical Cord Blood of Newborns With Prenatal Exposure to Crack Cocaine(2021) BAPTISTA, Talita; AZEREDO, Lucas Araujo de; ZAPARTE, Aline; VIOLA, Thiago Wendt; CORAL, Sayra Catalina; NAGAI, Maria Aparecida; MANGONE, Flavia Rotea; PAVANELLI, Ana Carolina; SCHUCH, Jaqueline B.; MARDINI, Victor; SZOBOT, Claudia M.; GRASSI-OLIVEIRA, RodrigoBackground Prenatal cocaine exposure (PCE) is associated with behavioral, cognitive, and social consequences in children that might persist into later development. However, there are still few data concerning epigenetic mechanisms associated with the effects of gestational cocaine exposure, particularly in human newborns. Aims We investigated the effects of PCE on DNA methylation patterns of the Oxytocin Receptor (OXTR) gene in the umbilical cord blood (UCB). The relationship between UCB DNA methylation levels and the severity of the mother's cocaine use during pregnancy was also evaluated. Methods In this cross-sectional study, 28 UCB samples of newborns with a history of crack cocaine exposure in utero and 30 UCB samples of non-exposed newborns (NEC) were compared for DNA methylation levels at two genomic loci located in exon III of the OXTR gene (OXTR1 and OXTR2) through pyrosequencing. Maternal psychopathology was investigated using the Mini International Neuropsychiatric Interview, and substance use characteristics and addiction severity were assessed using the Smoking and Substance Involvement Screening Test (ASSIST). Results No differences between newborns with a history of PCE and NEC were observed in OXTR1 or OXTR2 DNA methylation levels. However, regression analyses showed that maternal addiction severity for crack cocaine use predicted OXTR1 DNA methylation in newborns. Conclusion These data suggest that OXTR methylation levels in the UCB of children are affected by the severity of maternal crack cocaine usage. Larger studies are likely to detect specific changes in DNA methylation relevant to the consequences of PCE.
- Effects of intrauterine exposure to concentrated ambient particles on allergic sensitization in juvenile mice(2021) BRITO, Jose Mara de; AMEIDA, Francine Maria de; ARANTES-COSTA, Fernanda Magalhaes; GUIMARAES, Eliane Tigre; MORGAN, Adriana; MANGONE, Flavia Rotea; PAVANELLI, Ana Carolina; NAGAI, Maria Aparecida; VIEIRA, Rodolfo P.; MACCHIONE, Mariangela; MAUAD, ThaisIntrauterine exposure to particulate matter (PM) has been associated with an increased risk of asthma development, which may differ by the age of asthma onset, sex, and pollutant concentration. To investigate the pulmonary effects of in utero exposure to concentrated urban ambient particles (CAPs) in response to house dust mite (HDM) sensitization in juvenile mice. Mice were exposed to CAPs (600 mu g/m(3) PM2.5) during the gestational period. Twenty-two-day postnatal mice were sensitized with HDM (100 mu g, intranasally, 3 times per week). Airway responsiveness (AHR), serum immunoglobulin, and lung inflammation were assessed after 43 days of the postnatal period. Female (n = 47) and male (n = 43) mice were divided into four groups as follows: (1) FA: not exposed to CAPs; (2) CAPs: exposed to CAPs; (3) HDM: sensitized to HDM; and (4) CAPs+HDM: exposed to CAPs and HDM-sensitized. PM2.5 exposure did not worsen lung hyperresponsiveness or allergic inflammation in sensitized animals. The levels of the lung cytokines IL-4, TNF-alpha, and IL-2 were differentially altered in male and female animals. Males presented hyporesponsiveness and increased lung macrophagic inflammation. There were no epigenetic changes in the IL-4 gene. In conclusion, intrauterine exposure ambient PM2.5 did not worsened allergic pulmonary susceptibility but affected the pulmonary immune profile and lung function, which differed by sex.
- Cocaine use disorder effects on blood oxytocin levels and OXTR DNA methylation(2023) SOUZA, Manasses Soares; SANVICENTE-VIEIRA, Breno; ZAPARTE, Aline; BAPTISTA, Talita; NAGAI, Maria Aparecida; MANGONE, Flavia Rotea; PAVANELLI, Ana Carolina; VIOLA, Thiago Wendt; GRASSI-OLIVEIRA, RodrigoSubstance use disorders have been associated with alterations in the oxytocinergic system, but few studies have investigated both the peptide and epigenetic mechanisms potentially implicated in the regulation of oxytocin receptor. In this study, we compared plasma oxytocin and blood DNA methylation in the OXTR gene between people with and without cocaine use disorder (CUD). We measured the oxytocin levels of 51 people with CUD during acute abstinence and of 30 healthy controls using an enzyme immunoassay. The levels of DNA methylation in four CpG sites at exon III of the OXTR gene were evaluated in a subsample using pyrosequencing. The Addiction Severity Index was used to assess clinical characteristics. We found higher oxytocin levels in men with CUD (56.5 pg/mL; 95% CI: 48.2-64.7) than in control men (33.6 pg/mL; 95% CI: 20.7-46.5), while no differences between women with and without CUD were detected. With a moderate effect size, the interaction effect between group and sex remained significant when controlling for height, weight and age data. A positive correlation in the CUD sample was found between oxytocin levels and days of psychological suffering prior to treatment enrollment. No group differences were observed regarding DNA methylation data. This suggests that CUD is associated with higher peripheral oxytocin levels in men during acute abstinence. This finding may be considered in future studies that aim at using exogenous oxytocin as a potential treatment for cocaine addiction.
- Interrelated but Not Time-Aligned Response in Myogenic Regulatory Factors Demethylation and mRNA Expression after Divergent Exercise Bouts(2023) TELLES, Guilherme Defante; LIBARDI, Cleiton Augusto; CONCEICAO, Miguel Soares; VECHIN, Felipe Cassaro; LIXANDRAO, Manoel Emilio; MANGONE, Flavia Regina Rotea; PAVANELLI, Ana Carolina; NAGAI, Maria Aparecida; CAMERA, Donny Michael; HAWLEY, John A.; UGRINOWITSCH, CarlosIntroductionDNA methylation regulates exercise-induced changes in the skeletal muscle transcriptome. However, the specificity and the time course responses in the myogenic regulatory factors DNA methylation and mRNA expression after divergent exercise modes are unknown.PurposeThis study aimed to compare the time course changes in DNA methylation and mRNA expression for selected myogenic regulatory factors (MYOD1, MYF5, and MYF6) immediately after, 4 h after, and 8 h after a single bout of resistance exercise (RE), high-intensity interval exercise (HIIE), and concurrent exercise (CE).MethodsNine healthy but untrained males (age, 23.9 +/- 2.8 yr; body mass, 70.1 +/- 14.9 kg; peak oxygen uptake [V?O-2peak], 41.4 +/- 5.2 mL center dot kg(-1)center dot min(-1); mean +/- SD) performed a counterbalanced, randomized order of RE (4 x 8-12 repetition maximum), HIIE (12 x 1 min sprints at V?O-2peak running velocity), and CE (RE followed by HIIE). Skeletal muscle biopsies (vastus lateralis) were taken before (REST) immediately (0 h), 4 h, and 8 h after each exercise bout.ResultsCompared with REST, MYOD1, MYF5, and MYF6, mean methylation across all CpGs analyzed was reduced after 4 and 8 h in response to all exercise protocols (P < 0.05). Reduced levels of MYOD1 methylation were observed after HIIE and CE compared with RE (P < 0.05). Compared with REST, all exercise bouts increased mRNA expression over time (MYOD1 at 4 and 8 h, and MYF6 at 4 h; P < 0.05). MYF5 mRNA expression was lower after 4 h compared with 0 h and higher at 8 h compared with 4 h (P < 0.05).ConclusionsWe observed an interrelated but not time-aligned response between the exercise-induced changes in myogenic regulatory factors demethylation and mRNA expression after divergent exercise modes. Despite divergent contractile stimuli, changes in DNA methylation and mRNA expression in skeletal muscle were largely confined to the late (4-8 h) recovery period and similar between the different exercise challenges.
bookPart Técnicas de biologia molecular aplicadas à pesquisa oncológica(2022) PAVANELLI, Ana Carolina; PEREIRA, Marisa Alessandra; PASINI, Fátima Solange; MANGONE, Flávia Regina Rotea