Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320.
Nat Cell Biol, 2011/12/18;14(2):159-67.
Bronisz A[1], Godlewski J, Wallace JA, Merchant AS, Nowicki MO, Mathsyaraja H, Srinivasan R, Trimboli AJ, Martin CK, Li F, Yu L, Fernandez SA, Pécot T, Rosol TJ, Cory S, Hallett M, Park M, Piper MG, Marsh CB, Yee LD, Jimenez RE, Nuovo G, Lawler SE, Chiocca EA, Leone G, Ostrowski MC
Affiliations
PMID: 22179046DOI: 10.1038/ncb2396
Impact factor: 28.213
Abstract
PTEN (Phosphatase and tensin homolog deleted on chromosome 10) expression in stromal fibroblasts suppresses epithelial mammary tumours, but the underlying molecular mechanisms remain unknown. Using proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2) are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumour angiogenesis and tumour-cell invasion. Expression of the Pten-miR-320-Ets2-regulated secretome distinguished human normal breast stroma from tumour stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumour-suppressor axis that acts in stromal fibroblasts to reprogramme the tumour microenvironment and curtail tumour progression.
MeSH terms
Animals; Blotting, Western; Breast Neoplasms; COS Cells; Cell Line, Tumor; Chlorocebus aethiops; Female; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Mammary Neoplasms, Experimental; Mice; Mice, Knockout; MicroRNAs; Oligonucleotide Array Sequence Analysis; PTEN Phosphohydrolase; Proto-Oncogene Protein c-ets-2; RNA Interference; Reverse Transcriptase Polymerase Chain Reaction; Stromal Cells; Tumor Microenvironment
More resources
Full text:
Europe PubMed Central; PubMed Central
EndNote: Download