FLAVIA REGINA ROTEA MANGONE

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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

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  • article 49 Citação(ões) na Scopus
    Decreased expression of ADAMTS-1 in human breast tumors stimulates migration and invasion
    (2013) FREITAS, Vanessa M.; AMARAL, Jonatas Bussador do; SILVA, Thaiomara A.; SANTOS, Emerson S.; MANGONE, Flavia R.; PINHEIRO, Joao de Jesus; JAEGER, Ruy G.; NAGAI, Maria A.; MACHADO-SANTELLI, Glaucia Maria
    Background: ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motifs) is a member of the ADAMTS family of metalloproteases. Here, we investigated mRNA and protein levels of ADAMTS-1 in normal and neoplastic tissues using qPCR, immunohistochemistry and immunoblot analyses, and we addressed the role of ADAMTS-1 in regulating migration, invasion and invadopodia formation in breast tumor cell lines. Results: In a series of primary breast tumors, we observed variable levels of ADAMTS-1 mRNA expression but lower levels of ADAMTS-1 protein expression in human breast cancers as compared to normal tissue, with a striking decrease observed in high-malignancy cases (triple-negative for estrogen, progesterone and Her-2). This result prompted us to analyze the effect of ADAMTS-1 knockdown in breast cancer cells in vitro. MDA-MB-231 cells with depleted ADAMTS-1 expression demonstrated increased migration, invasion and invadopodia formation. The regulatory mechanisms underlying the effects of ADAMTS-1 may be related to VEGF, a growth factor involved in migration and invasion. MDA-MB-231 cells with depleted ADAMTS-1 showed increased VEGF concentrations in conditioned medium capable of inducing human endothelial cells (HUVEC) tubulogenesis. Furthermore, expression of the VEGF receptor (VEGFR2) was increased in MDA-MB-231 cells as compared to MCF7 cells. To further determine the relationship between ADAMTS-1 and VEGF regulating breast cancer cells, MDA-MB-231 cells with reduced expression of ADAMTS-1 were pretreated with a function-blocking antibody against VEGF and then tested in migration and invasion assays; both were partially rescued to control levels. Conclusions: ADAMTS-1 expression was decreased in human breast tumors, and ADAMTS-1 knockdown stimulated migration, invasion and invadopodia formation in breast cancer cells in vitro. Therefore, this series of experiments suggests that VEGF is involved in the effects mediated by ADAMTS-1 in breast cancer cells.
  • article 3 Citação(ões) na Scopus
    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 Aparecida
    Purpose 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.
  • conferenceObject
    SMC6 down-regulation: marker of genetic instability and poor outcome in breast cancer
    (2023) MANGONE, Flavia R. Rotea; KREPISCHI, Ana Cristina V.; CARRARO, Dirce M.; NAGAI, Maria A.
  • article 3 Citação(ões) na Scopus
    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.
  • conferenceObject
    Genomic profile of primary non-small cell lung cancer and matched mediastinal lymph nodes by next-generation sequencing: a pilot study
    (2022) ANTONANGELO, L.; FARIA, C. S.; TERRA, R. M.; NASCIMENTO, E. C. T. do; MELLO, E. S. de; MANGONE, F. R. R.; NAGAI, M. A.; AGATI, M. E. M.; CAPELOZZI, V. L.
  • article
    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.
  • article 7 Citação(ões) na Scopus
    Circulating Plasma miRNA and Clinical/Hemodynamic Characteristics Provide Additional Predictive Information About Acute Pulmonary Thromboembolism, Chronic Thromboembolic Pulmonary Hypertension and Idiopathic Pulmonary Hypertension
    (2021) FABRO, Alexandre Todorovic; MACHADO-RUGOLO, Juliana; BALDAVIRA, Camila Machado; PRIETO, Tabatha Gutierrez; FARHAT, Cecilia; MANGONE, Flavia Regina Rotea; BATAH, Sabrina Setembre; CRUVINEL, Heloisa Resende; ALDA, Maiara Almeida; MONTEIRO, Jhonatas Sirino; PADUA, Adriana Inacio; MORAIS, Sirlei Siani; OLIVEIRA, Rogerio Antonio de; SANTOS, Marcel Koenigkam; BADDINI-MARTINEZ, Jose Antonio; SETUBAL, Joao Carlos; RAINHO, Claudia Aparecida; YOO, Hugo Hyung Bok; SILVA, Pedro Leme; NAGAI, Maria Aparecida; CAPELOZZI, Vera Luiza
    Idiopathic pulmonary artery hypertension (IPAH), chronic thromboembolic pulmonary hypertension (CTEPH), and acute pulmonary embolism (APTE) are life-threatening cardiopulmonary diseases without specific surgical or medical treatment. Although APTE, CTEPH and IPAH are different pulmonary vascular diseases in terms of clinical presentation, prevalence, pathophysiology and prognosis, the identification of their circulating microRNA (miRNAs) might help in recognizing differences in their outcome evolution and clinical forms. The aim of this study was to describe the APTE, CTEPH, and IPAH-associated miRNAs and to predict their target genes. The target genes of the key differentially expressed miRNAs were analyzed, and functional enrichment analyses were carried out. The miRNAs were detected using RT-PCR. Finally, we incorporated plasma circulating miRNAs in baseline and clinical characteristics of the patients to detect differences between APTE and CTEPH in time of evolution, and differences between CTEPH and IPAH in diseases form. We found five top circulating plasma miRNAs in common with APTE, CTEPH and IPAH assembled in one conglomerate. Among them, miR-let-7i-5p expression was upregulated in APTE and IPAH, while miRNA-320a was upregulated in CTEP and IPAH. The network construction for target genes showed 11 genes regulated by let-7i-5p and 20 genes regulated by miR-320a, all of them regulators of pulmonary arterial adventitial fibroblasts, pulmonary artery endothelial cell, and pulmonary artery smooth muscle cells. AR (androgen receptor), a target gene of hsa-let-7i-5p and has-miR-320a, was enriched in pathways in cancer, whereas PRKCA (Protein Kinase C Alpha), also a target gene of hsa-let-7i-5p and has-miR-320a, was enriched in KEGG pathways, such as pathways in cancer, glioma, and PI3K-Akt signaling pathway. We inferred that CTEPH might be the consequence of abnormal remodeling in APTE, while unbalance between the hyperproliferative and apoptosis-resistant phenotype of pulmonary arterial adventitial fibroblasts, pulmonary artery endothelial cell and pulmonary artery smooth muscle cells in pulmonary artery confer differences in IPAH and CTEPH diseases form. We concluded that the incorporation of plasma circulating let-7i-5p and miRNA-320a in baseline and clinical characteristics of the patients reinforces differences between APTE and CTEPH in outcome evolution, as well as differences between CTEPH and IPAH in diseases form.
  • article 5 Citação(ões) na Scopus
    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.
  • article 36 Citação(ões) na Scopus
    A gene expression profile related to immune dampening in the tumor microenvironment is associated with poor prognosis in gastric adenocarcinoma
    (2014) PASINI, Fatima Solange; ZILBERSTEIN, Bruno; SNITCOVSKY, Igor; ROELA, Rosimeire Aparecida; MANGONE, Flavia R. Rotea; RIBEIRO JR., Ulysses; NONOGAKI, Suely; BRITO, Glauber Costa; CALLEGARI, Giovanna D.; CECCONELLO, Ivan; ALVES, Venancio Avancini Ferreira; ELUF-NETO, Jose; CHAMMAS, Roger; FEDERICO, Miriam Hatsue Honda
    The TNM Classification of Malignant Tumours (TNM) staging system is the primary means of determining a prognosis for gastric adenocarcinoma (GC). However, tumor behavior in the individual patient is unpredictable and in spite of treatment advances, a classification of 'advanced stage' still portends a poor prognosis. Thus, further insights from molecular analyses are needed for better prognostic stratification and determination of new therapeutic targets. A total of fifty-one fresh frozen tumor samples from patients with histopathologically confirmed diagnoses of GC, submitted to surgery with curative intent, were included in the study. Total RNA was extracted from an initial group of fifteen samples matched for known prognostic factors, categorized into two subgroups, according to patient overall survival: poor (< 24 months) or favorable (at or above 24 months), and hybridized to Affymetrix Genechip human genome U133 plus 2.0 for genes associated with prognosis selection. Thirteen genes were selected for qPCR validation using those initial fifteen samples plus additional thirty-six samples. A total of 108 genes were associated with poor prognosis, independent of tumor staging. Using systems biology, we suggest that this panel reflects the dampening of immune/inflammatory response in the tumor microenvironment level and a shift to Th2/M2 activity. A gene trio (OLR1, CXCL11 and ADAMDEC1) was identified as an independent marker of prognosis, being the last two markers validated in an independent patient cohort. We determined a panel of three genes with prognostic value in gastric cancer, which should be further investigated. A gene expression profile suggestive of a dysfunctional inflammatory response was associated with unfavorable prognosis.