title: Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320.
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.
authors.affiliation: Tumor Microenvironment Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bronisz
authors.forename: J
authors.initials: J
authors.lastname: Godlewski
authors.forename: J A
authors.initials: JA
authors.lastname: Wallace
authors.forename: A S
authors.initials: AS
authors.lastname: Merchant
authors.forename: M O
authors.initials: MO
authors.lastname: Nowicki
authors.forename: H
authors.initials: H
authors.lastname: Mathsyaraja
authors.forename: R
authors.initials: R
authors.lastname: Srinivasan
authors.forename: A J
authors.initials: AJ
authors.lastname: Trimboli
authors.forename: C K
authors.initials: CK
authors.lastname: Martin
authors.forename: F
authors.initials: F
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.forename: S A
authors.initials: SA
authors.lastname: Fernandez
authors.forename: T
authors.initials: T
authors.lastname: Pécot
authors.forename: T J
authors.initials: TJ
authors.lastname: Rosol
authors.forename: S
authors.initials: S
authors.lastname: Cory
authors.forename: M
authors.initials: M
authors.lastname: Hallett
authors.forename: M
authors.initials: M
authors.lastname: Park
authors.forename: M G
authors.initials: MG
authors.lastname: Piper
authors.forename: C B
authors.initials: CB
authors.lastname: Marsh
authors.forename: L D
authors.initials: LD
authors.lastname: Yee
authors.forename: R E
authors.initials: RE
authors.lastname: Jimenez
authors.forename: G
authors.initials: G
authors.lastname: Nuovo
authors.forename: S E
authors.initials: SE
authors.lastname: Lawler
authors.forename: E A
authors.initials: EA
authors.lastname: Chiocca
authors.forename: G
authors.initials: G
authors.lastname: Leone
authors.forename: M C
authors.initials: MC
authors.lastname: Ostrowski
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: C494070:Ets2 protein, mouse; D035683:MicroRNAs; C541056:Mirn320 microRNA, mouse; D050787:Proto-Oncogene Protein c-ets-2; D051059:PTEN Phosphohydrolase