Breast cancer tissue slices as a model for evaluation of response to rapamycin

Autor(es):Mostrar menos -

Giorgi Grosso, Stana Helena ^[1] ; Hirata Katayama, Maria Lucia ^[2] ; Roela, Rosimeire Aparecida ^[2] ; Nonogaki, Suely ^[3] ; Soares, Fernando Augusto ^[4] ; Brentani, Helena ^[5] ; Lima, Leandro ^[6] ; Azevedo Koike Folgueira, Maria Aparecida ^[2] ; Logullo Waitzberg, Angela Flavia ^[7] ; Pasini, Faima Solange ^[2] ; Guedes Sampaio Goes, Joao Carlos ^[1] ; Mitzi Brentani, M. ^[2]

Afiliação do(s) autor(es)

^[1] Inst Brasileiro Controle Canc, BR-03102002 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Dept Radiol & Oncol, Disciplina Oncol LIM 24, BR-01246903 Sao Paulo - Brazil

^[3] Adolfo Lutz Inst, Lab Imunohistoquim, Div Patol, BR-01246902 Sao Paulo - Brazil

^[4] Hosp A C Camargo, BR-01509010 Sao Paulo - Brazil

^[5] Univ Sao Paulo, Fac Med, Dept Psiquiatria LIM 23, Sao Paulo - Brazil

^[6] Hosp AC Camargo Fund Antonio Prudente, CIPE, Lab Bioinformat & Bioestat, BR-01508010 Sao Paulo - Brazil

^[7] Univ Fed Sao Paulo, Dept Patol, BR-04023900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Cell and Tissue Research; v. 352, n. 3, p. 671-684, JUN 2013.
• Citações Web of Science: 7

Resumo

Rapamycin 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. (AU)

• Processo FAPESP: 09/10088-7 - Expressão gênica de fibroblastos associados a carcinomas de mama classificados em subtipos de acordo com receptores de estrógeno e progesterona e C-ERBB2
• Beneficiário: Maria Mitzi Brentani
• Linha de fomento: Auxílio à Pesquisa - Temático