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Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320
A Bronisz1, J Godlewski, J A Wallace
1Tumor Microenvironment Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Nature Cell Biology
|December 20, 2011
Summary
Loss of PTEN in breast stroma activates a cancer-promoting secretome via miR-320 and ETS2. This reprogramming of the tumor microenvironment drives breast cancer progression and recurrence.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- PTEN (Phosphatase and tensin homolog deleted on chromosome 10) expression in stromal fibroblasts normally suppresses epithelial mammary tumors.
- The precise molecular mechanisms by which PTEN loss in stromal fibroblasts promotes tumor progression are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which PTEN loss in mammary stromal fibroblasts contributes to breast tumor progression.
- To identify key molecular players and pathways involved in the reprogramming of the tumor microenvironment by Pten-deficient stromal fibroblasts.
Main Methods:
- Proteomic and expression profiling analyses were employed to investigate changes in Pten-deleted mammary stromal fibroblasts.
- Investigated the role of microRNA-320 (miR-320) and its target ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2) in mediating the effects of Pten loss.
Main Results:
- Pten loss in mammary stromal fibroblasts activates an oncogenic secretome that reprograms the tumor microenvironment.
- Downregulation of miR-320 and upregulation of ETS2 are critical events driving this oncogenic secretome.
- The Pten-miR-320-Ets2-regulated secretome promotes tumor angiogenesis and invasion, and distinguishes human normal from tumor stroma, correlating with patient recurrence.
Conclusions:
- miR-320 is a crucial component of the PTEN tumor suppressor pathway acting in stromal fibroblasts.
- PTEN-deficient stromal fibroblasts reprogram the tumor microenvironment through a miR-320/ETS2-dependent secretome, promoting breast cancer progression.
- This pathway represents a potential therapeutic target for curtailing breast tumor progression.
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