期刊
NATURE
卷 461, 期 7267, 页码 1084-U181出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature08486
关键词
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资金
- National Institutes of Health [R01CA85619, R01HD47470, P01CA097189, R01CA053271]
- Komen Breast Cancer Foundation
- Evelyn Simmers Charitable Trust
- Terry Fox New Frontiers Group Grant
- Natural Science and Engineering Research Council of Canada Discovery Grants Program
- Department of Defense Pre- doctoral Fellowships
- Department of Defense Postdoctoral Fellowship
- Pew Charitable Trusts Scholar Award
- Leukemia and Lymphoma Society Scholar Award
- Diane and Sal Guerrera Chair in Cancer Genetics at McGill University
The tumour stroma is believed to contribute to some of the most malignant characteristics of epithelial tumours. However, signalling between stromal and tumour cells is complex and remains poorly understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumours. This was associated with the massive remodelling of the extracellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumours ameliorated disruption of the tumour microenvironment and was sufficient to decrease tumour growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumour stroma of patients with breast cancer. These findings identify the Pten-Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.
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