Abstract 512: Reprogramming of the tumor microenvironment by stromal Pten-regulated miR-320

Abstract

Abstract The tumor microenvironment is increasingly recognized as an essential collaborator for tumor cell growth and dissemination. However, our understanding of how the dialogue between stroma and tumor occurs at the molecular level is rudimentary. Recently, we showed that the genetic inactivation of Phosphatase and tensin homolog deleted on chromosome ten (Pten) in mouse mammary fibroblasts (MMFs) accelerates the initiation, progression and malignant transformation of mammary epithelial tumors and that this was associated with the activation of the transcription factor v-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2). In order to provide a molecular framework that defines how Pten deletion in MMFs, reprograms expression of other cells in the tumor microenvironment we carried out global miR profiling of Pten-/- MMFs. Among several significant changes in the miR expression profile compared with wild type MMFs, a novel and highly significant down-regulation of miR-320 was detected. We found that miR-320 in Pten-/- MMFs acted as a tumor suppressor to inhibit epithelial tumor growth in vivo, providing the first evidence for tumor suppressive functions of miRs outside the confines of the tumor cell. Proteomic analysis of the extracellular matrix showed that down-regulation of miR-320 in stromal fibroblasts induces a tumor-promoting secretome that incites profound changes in endothelial and epithelial cell phenotypes typical of malignant tumors. We found ETS2 as a direct target of miR-320 that was largely responsible for regulating the expression of the fibroblast-specific secretome. Multispectral imaging of human invasive breast carcinoma samples revealed a positive correlation between PTEN and miR-320 downregulation and negative correlation between miR-320 and ETS2 expression. Importantly, we show that expression of the miR-320/ETS2 regulated secretome can distinguish tumor stroma form normal breast stroma in breast cancer patients and can retrospectively predict patient outcome in multiple breast cancer gene expression data sets.These results extend the concept of miR function beyond the tumor cell boundary and define a network of communication between tumor fibroblasts and tumor cells that can potentially be targeted in human cancer. This work reveals miR-320 as a critical component of the Pten tumor suppressor axis that acts in stromal fibroblasts to reprogram the tumor microenvironment and curtail tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 512. doi:10.1158/1538-7445.AM2011-512