Abstract
Abstract Background: mTOR (mammalian target of rapamycin) is a serine threonine kinase, member of the AKT/PI3K pathway, which is involved in multiple biologic functions such as transcription, translation, protein degradation and ribosome biogenesis. The activation of this protein results in phosphorilation and activation of S6K1 and 4EBP1. Rapamycin is a potent fungicide, immunossupressive and anti-cancer agent that inhibits the mTOR pathway and is an emerging cancer therapeutic. Objective: The aim of this study was to determine genes regulated by rapamycin in samples of ductal invasive breast cancer to identify novel markers of rapamycin response. Material and Methods: Inhibition of some elements of AKT pathway was assessed by immunohistochemistry in samples of breast carcinoma maintained in organ culture of fresh cut slices that preserves the interaction between epithelium and stroma before and after treatment with rapamycin. Additionally changes of the gene expression profile was analyzed by microarray in these samples subdivided in positive and negative Erb-B2. Results: Immunohistochemistry analysis indicated a significant decrease of 4EBP1 in the samples of tumor treated with rapamycin compared with the control cases. Microarray analysis revealed that few common genes were regulated in both tumor types but rapamycin affected the expression of genes mainly involved in cellular transcription and translation in both groups. To confirm the results obtained through microarray technique, RT-PCR analysis was performed in independent samples and we validated the genes WWOX, EXT1 and GTF2E2 in 60% of our cases. Over expression of the autophagy related beclin 1 indicated a contribution of autophagy to cytotoxicity of rapamycin. Conclusion: The organ culture represents a simple method to determine the effects of rapamycin and using gene profile analysis, novel genes that possible could be used as markers of mTOR inhibition were identified. Supported by FAPESP nº 04/04607-8 Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6129.
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