Faculty Collaboration Database

Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat Cell Biol 2011 Dec 18;14(2):159-67

Date

12/20/2011

Pubmed ID

22179046

Pubmed Central ID

PMC3271169

DOI

10.1038/ncb2396

Scopus ID

2-s2.0-84856464305 (requires institutional sign-in at Scopus site)   245 Citations

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.

Author List

Bronisz A, 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

Authors

Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of Wisconsin
Anthony J. Trimboli PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blotting, Western
Breast Neoplasms
COS Cells
Cell Line, Tumor
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