MARIA MITZI BRENTANI
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/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina
19 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 19
- Somatic mutations in early onset luminal breast cancer(2018) ENCINAS, G.; SABELNYKOVA, V. Y.; LYRA, E. C. de; KATAYAMA, M. L. H.; MAISTRO, S.; VALLE, P. W. M. V.; PEREIRA, G. F. L.; RODRIGUES, L. M.; SERIO, P. A. M. P.; GOUVêA, A. C. R. C. de; GEYER, F. C.; BASSO, R. A.; PASINI, F. S.; DIZ, M. P. E.; BRENTANI, M. M.; GóES, J. C. G. S.; CHAMMAS, R.; BOUTROS, P. C.; FOLGUEIRA, M. A. A. K.Breast cancer arising in very young patients may be biologically distinct; however, these tumors have been less well studied. We characterized a group of very young patients (≤ 35 years) for BRCA germline mutation and for somatic mutations in luminal (HER2 negative) breast cancer. Thirteen of 79 unselected very young patients were BRCA1/2 germline mutation carriers. Of the non-BRCA tumors, eight with luminal subtype (HER2 negative) were submitted for whole exome sequencing and integrated with 29 luminal samples from the COSMIC database or previous literature for analysis. We identified C to T single nucleotide variants (SNVs) as the most common base-change. A median of six candidate driver genes was mutated by SNVs in each sample and the most frequently mutated genes were PIK3CA, GATA3, TP53 and MAP2K4. Potential cancer drivers affected in the present non-BRCA tumors include GRHL2, PIK3AP1, CACNA1E, SEMA6D, SMURF2, RSBN1 and MTHFD2. Sixteen out of 37 luminal tumors (43%) harbored SNVs in DNA repair genes, such as ATR, BAP1, ERCC6, FANCD2, FANCL, MLH1, MUTYH, PALB2, POLD1, POLE, RAD9A, RAD51 and TP53, and 54% presented pathogenic mutations (frameshift or nonsense) in at least one gene involved in gene transcription. The differential biology of luminal early-age onset breast cancer needs a deeper genomic investigation. © Encinas et al.
- Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer(2019) KATAYAMA, Maria Lucia Hirata; VIEIRA, Rene Aloisio Costa; ANDRADE, Victor Piana; ROELA, Rosimeire Aparecida; LIMA, Luiz Guilherme Cernaglia Aureliano; KERR, Ligia Maria; CAMPOS, Adriano Polpo de; PEREIRA, Carlos Alberto de Braganca; SERIO, Pedro Adolpho de Menezes Pacheco; ENCINAS, Giselly; MAISTRO, Simone; PETRONI, Matheus de Almeida Leite; BRENTANI, Maria Mitzi; FOLGUEIRA, Maria Aparecida Azevedo KoikeBreast cancer stromal compartment, may influence responsiveness to chemotherapy. Our aim was to detect a stromal cell signature (using a direct approach of microdissected stromal cells) associated with response to neoadjuvant chemotherapy (neoCT) in locally advanced breast cancer (LABC). The tumor samples were collected from 44 patients with LABC (29 estrogen receptor (ER) positive and 15 ER negative) before the start of any treatment. Neoadjuvant chemotherapy consisted of doxorubicin and cyclophosphamide, followed by paclitaxel. Response was defined as downstaging to maximum ypT1a-b/ypN0. The stromal cells, mainly composed of fibroblast and immune cells, were microdissected from fresh frozen tumor samples and gene expression profile was determined using Agilent SurePrint G3 Human Gene Expression microarrays. Expression levels were compared using MeV (MultiExperiment Viewer) software, applying SAM (significance analysis of microarrays). To classify samples according to tumor response, the order of median based on confidence statements (MedOr) was used, and to identify gene sets correlated with the phenotype downstaging, gene set enrichment analysis (GSEA). Nine patients presented disease downstaging. Eleven sequences (FDR 17) were differentially expressed, all of which (except H2AFJ) more expressed in responsive tumors, including PTCHD1 and genes involved in abnormal cytotoxic T cell physiology, TOX, LY75, and SH2D1A. The following four pairs of markers could correctly classify all tumor samples according to response: PTCHD1/PDXDC2P, LOC100506731/NEURL4, SH2D1A/ENST00000478672, and TOX/H2AFJ. Gene sets correlated with tumor downstaging (FDR < 0.01) were mainly involved in immune response or lymphocyte activation, including CD47, LCK, NCK1, CD24, CD3E, ZAP70, FOXP3, and CD74, among others. In locally advanced breast cancer, stromal cells may present specific features of immune response that may be associated with chemotherapy response.
- Somatic mutations in breast and serous ovarian cancer young patients: a systematic review and meta-analysis(2015) ENCINAS, Giselly; MAISTRO, Simone; PASINI, Fatima Solange; KATAYAMA, Maria Lucia Hirata; BRENTANI, Maria Mitzi; BOCK, Geertruida Hendrika de; FOLGUEIRA, Maria Aparecida Azevedo KoikeObjective: our aim was to evaluate whether somatic mutations in five genes were associated with an early age at presentation of breast cancer (BC) or serous ovarian cancer (SOC). Methods: COSMIC database was searched for the five most frequent somatic mutations in BC and SOC. A systematic review of PubMed was performed. Young age for BC and SOC patients was set at <= 35 and <= 40 years, respectively. Age groups were also classified in <30years and every 10 years thereafter. Results: twenty six (1,980 patients, 111 younger) and 16 studies (598, 41 younger), were analyzed for BC and SOC, respectively. In BC, PIK3CA wild type tumor was associated with early onset, not confirmed in binary regression with estrogen receptor (ER) status. In HER2-negative tumors, there was increased frequency of PIK3CA somatic mutation in older age groups; in ER-positive tumors, there was a trend towards an increased frequency of PIK3CA somatic mutation in older age groups. TP53 somatic mutation was described in 20% of tumors from both younger and older patients; PTEN, CDH1 and GATA3 somatic mutation was investigated only in 16 patients and PTEN mutation was detected in one of them. In SOC, TP53 somatic mutation was rather common, detected in more than 50% of tumors, however, more frequently in older patients. Conclusion: frequency of somatic mutations in specific genes was not associated with early-onset breast cancer. Although very common in patients with serous ovarian cancer diagnosed at all ages, TP53 mutation was more frequently detected in older women.
- Gene Expression Profile in Response to Doxorubicin-Rapamycin Combined Treatment of HER-2-Overexpressing Human Mammary Epithelial Cell Lines(2012) TRAPE, Adriana Priscila; KATAYAMA, Maria Lucia Hirata; ROELA, Rosimeire Aparecida; BRENTANI, Helena; RAVACCI, Graziela Rosa; LIMA, Leandro de Araujo; BRENTANI, Maria MitziHER-2-positive breast cancers frequently sustain elevated AKT/mTOR signaling, which has been associated with resistance to doxorubicin treatment. Here, we investigated whether rapamycin, an mTOR inhibitor, increased the sensitivity to doxorubicin therapy in two HER-2-overexpressing cell lines: C5.2, which was derived from the parental HB4a by transfection with HER-2 and SKBR3, which exhibits HER-2 amplification. The epithelial mammary cell line HB4a was also analyzed. The combined treatment using 20 nmol/L of rapamycin and 30 nmol/L of doxorubicin arrested HB4a and C5.2 cells in S to G(2)-M, whereas SKBR3 cells showed an increase in the G(0)-G(1) phase. Rapamycin increased the sensitivity to doxorubicin in HER-2-overexpressing cells by approximately 2-fold, suggesting that the combination displayed a more effective antiproliferative action. Gene expression profiling showed that these results might reflect alterations in genes involved in canonical pathways related to purine metabolism, oxidative phosphorylation, protein ubiquitination, and mitochondrial dysfunction. A set of 122 genes modulated by the combined treatment and specifically related to HER-2 overexpression was determined by finding genes commonly regulated in both C5.2 and SKBR3 that were not affected in HB4a cells. Network analysis of this particular set showed a smaller subgroup of genes in which coexpression pattern in HB4a cells was disrupted in C5.2 and SKBR3. Altogether, our data showed a subset of genes that might be more robust than individual markers in predicting the response of HER-2-overexpressing breast cancers to doxorubicin and rapamycin combination.
- Breast cancer tissue slices as a model for evaluation of response to rapamycin(2013) GROSSO, Stana Helena Giorgi; KATAYAMA, Maria Lucia Hirata; ROELA, Rosimeire Aparecida; NONOGAKI, Suely; SOARES, Fernando Augusto; BRENTANI, Helena; LIMA, Leandro; FOLGUEIRA, Maria Aparecida Azevedo Koike; WAITZBERG, Angela Flavia Logullo; PASINI, Faima Solange; GOES, Joao Carlos Guedes Sampaio; BRENTANI, M. MitziRapamycin is a selective inhibitor of the mammalian target of rapamycin (mTOR), a regulator kinase that integrates growth factors signaling via the phosphoinositide-3-kinase pathway and that has emerged as a novel therapeutic modality in breast cancer (BC). We propose a pre-clinical ""ex-vivo"" personalized organotypic culture of BC that preserves the microenvironment to evaluate rapamycin-mediated gene expression changes. Freshly excised ductal invasive BC slices, 400 mu m thick (n=30), were cultured in the presence or absence (control) of rapamycin (20 nM) for 24 h. Some slices were formalin-fixed for immunohistochemical determinations and some were processed for microarray analysis. Control slices in culture retained their tissue morphology and tissue viability (detected by BrdU uptake). The percentage of proliferating cells (assessed by Ki67) did not change up to 24 h of treatment. Immunohistochemical evaluation of p-AKT, p-mTOR, p-4EBP1 and p-S6K1 indicated that AKT/mTOR pathway activation was maintained during cultivation. For microarray analysis, slices were divided into two groups, according to the presence/absence of epidermal growth factor receptor-type 2 and analyzed separately. Limited overlap was seen among differentially expressed genes after treatment (P < 0.01) in both groups suggesting different responses to rapamycin between these BC subtypes. Ontology analysis indicated that genes involved in biosynthetic processes were commonly reduced by rapamycin. Our network analysis suggested that concerted expression of these genes might distinguish controls from treated slices. Thus, breast carcinoma slices constitute a suitable physiological tool to evaluate the short-term effects of rapamycin on the gene profile of individual BC samples.
- Specific upregulation of RHOA and RAC1 in cancer-associated fibroblasts found at primary tumor and lymph node metastatic sites in breast cancer(2015) ROZENCHAN, Patricia Bortman; PASINI, Fatima Solange; ROELA, Rosimeire A.; KATAYAMA, Maria Lucia Hirata; MUNDIM, Fiorita Gonzales Lopes; BRENTANI, Helena; LYRA, Eduardo C.; BRENTANI, Maria MitziThe importance of tumor-stromal cell interactions in breast tumor progression and invasion is well established. Here, an evaluation of differential genomic profiles of carcinoma-associated fibroblasts (CAFs) compared to fibroblasts derived from tissues adjacent to fibroadenomas (NAFs) revealed altered focal adhesion pathways. These data were validated through confocal assays. To verify the possible role of fibroblasts in lymph node invasion, we constructed a tissue microarray consisting of primary breast cancer samples and corresponding lymph node metastasis and compared the expression of adhesion markers RhoA and Rac1 in fibroblasts located at these different locations. Two distinct tissue microarrays were constructed from the stromal component of 43 primary tumors and matched lymph node samples, respectively. Fibroblasts were characterized for their expression of alpha-smooth muscle actin (alpha-SMA) and vimentin. Moreover, we verified the level of these proteins in the stromal compartment from normal adjacent tissue and in non-compromised lymph nodes. Our immunohistochemistry revealed that 59 % of fibroblasts associated with primary tumors and 41 % of the respective metastatic lymph nodes (p = 0.271) displayed positive staining for RhoA. In line with this, 57.1 % of fibroblasts associated with primary tumors presented Rac1-positive staining, and the frequency of co-positivity within the lymph nodes was 42.9 % (p = 0.16). Expression of RhoA and Rac1 was absent in fibroblasts of adjacent normal tissue and in compromised lymph nodes. Based on our findings that no significant changes were observed between primary and metastatic lymph nodes, we suggest that fibroblasts are active participants in the invasion of cancer cells to lymph nodes and support the hypothesis that metastatic tumor cells continue to depend on their microenvironment.
conferenceObject Stromal cell signature in luminal breast cancer associated with response to neoadjuvant chemotherapy.(2018) KATAYAMA, Maria Lucia H.; VIEIRA, Rene A. da Costa; ROELA, Rosimeire A.; ANDRADE, Victor P.; LIMA, Luiz Guilherme C. A. de; ENCINAS, Giselly; KERR, Ligia M.; MAISTRO, Simone; BRENTANI, M. Mitzi; FOLGUEIRA, Maria A. A. Koike- Gene expression profile of fibroblasts from different topographical origins in breast cancer patients(2012) VALLE, Paulo Roberto Del; KATAYAMA, Maria Lucia Hirata; ROZENCHAN, Patricia Bortman; MILANI, Cintia; LYRA, Eduardo Carneiro; PUGA, Renato; CARRARO, Dirce Maria; BRENTANI, M. Mitzi; FOLGUEIRA, Maria Aparecida Azevedo Koike
- Calcitriol supplementation effects on Ki67 expression and transcriptional profile of breast cancer specimens from post-menopausal patients(2014) URATA, Yuri Nagamine; LYRA, Eduardo Carneiro de; KATAYAMA, Maria Lucia Hirata; BASSO, Ricardo Alves; ASSIS, Paulo Eduardo Zuccolotto de; CARDOSO, Ana Paula Torres; ROELA, Rosimeire Aparecida; NONOGAKI, Suely; GOES, Joao Carlos Guedes Sampaio; BRENTANI, M. Mitzi; FOLGUEIRA, Maria Aparecida Azevedo KoikeBackground & aims: High concentration of 1,25(OH)(2)D-3 (50-100 nM), which cause hypercalcemia in vivo, induce the hormone transcriptional targets and exert antiproliferative effects in cultured breast cancer lineages, however, no studies investigated whether these effects might be reproduced in tumor specimens in vivo. Our aim was to evaluate the effects of calcitriol supplementation on the proliferative index (Ki67 expression) and gene expression profile of post-menopausal breast cancer samples. Methods & results: Tumor samples were collected from 33 patients, most of whom (87.5%) presenting 25(OH)D-3 insufficiency, before and after a short term calcitriol supplementation (0.50 mu g/day PO, for 30 days). Tumor dimension remained stable in ultrasound evaluations. A slight reduction in Ki67 immunoexpression was detected, however in only 10/32 post-calcitriol samples an expressively low proliferative index [Ln (%Ki67+) < 1] was achieved. Gene expression from 15 matched pre/post-supplementation samples was analyzed by microarray (U133 Plus 2.0 GeneChip, Affymetrix) and 15 genes were over-expressed in post-supplementation tumors, including FOS and EGR1, which were previously shown to be regulated by vitamin D. However, these results were not confirmed in another four breast cancer samples. Conclusions: Calcitriol supplementation is neither sufficient to expressively elicit an antiproliferative response nor to induce the hormone transcriptional signaling pathway in breast cancer specimens.
- Markers of breast cancer stromal fibroblasts in the primary tumour site associated with lymph node metastasis: a systematic review including our case series(2013) FOLGUEIRA, Maria Aparecida Azevedo Koike; MAISTRO, Simone; KATAYAMA, Maria Lucia Hirata; ROELA, Rosimeire Aparecida; MUNDIM, Fiorita Gonzales Lopes; NANOGAKI, Suely; BOCK, Geertruida H. de; BRENTANI, M. MitziCAFs (cancer-associated fibroblasts), the most abundant cell type in breast cancer stroma, produce a plethora of chemokines, growth factors and ECM (extracellular matrix) proteins, that may contribute to dissemination and metastasis. Axillary nodes are the first metastatic site in breast cancer; however, to the present date, there is no consensus of which specific proteins, synthesized by CAFs, might be related with lymph node involvement. The purpose of this study was to perform a systematic review of CAF biomarkers associated with the presence of regional metastasis. PubMed was searched using the words: 'breast cancer' and 'lymph node' and fibroblast or stroma or microenvironment. After exclusions, eight studies evaluating biomarkers immunoexpression in CAFs and lymph node status were selected. Biomarkers evaluated in these studies may be divided in two groups, according to their ontology: extracellular matrix components [MMP13 (matrix metalloproteinase 13), TIMP2 (tissue inhibitor of metalloproteinases-2), THBS1 (thrombospondin 1), LGALS1 (lectin, galactoside-binding, soluble, 1)] and response to wounding [PDPN (podoplanin), PLAU (plasminogen activator, urokinase), PLAUR (plasminogen activator, urokinase receptor), CAV1 (caveolin 1), THBS1, LGALS1]. A positive expression of MMP13 and LGALS1 in CAFs was associated with enhanced OR (odds ratio) for regional metastasis. Contrariwise, CAV1 positive staining of fibroblasts was associated with decreased OR for nodal involvement. Expression of MMP13, PDPN and CAV1 was further tested in a new series of 65 samples of invasive ductal breast carcinomas by immunohistochemistry and no association between biomarkers expression in CAFs and nodal status was found. It was suggested that breast cancer subtypes may differentially affect CAFs behaviour. It would be interesting to evaluate the prognostic significance of these biomarkers in CAFs from different tumour types.