1. Pten in stromal fibroblasts suppresses mammary epithelial tumours.
- Author
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Trimboli AJ, Cantemir-Stone CZ, Li F, Wallace JA, Merchant A, Creasap N, Thompson JC, Caserta E, Wang H, Chong JL, Naidu S, Wei G, Sharma SM, Stephens JA, Fernandez SA, Gurcan MN, Weinstein MB, Barsky SH, Yee L, Rosol TJ, Stromberg PC, Robinson ML, Pepin F, Hallett M, Park M, Ostrowski MC, and Leone G
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Extracellular Matrix metabolism, Gene Deletion, Gene Expression Regulation, Neoplastic, Humans, Immunity, Innate, Mammary Neoplasms, Experimental metabolism, Mammary Neoplasms, Experimental pathology, Mice, Mice, Transgenic, PTEN Phosphohydrolase deficiency, PTEN Phosphohydrolase genetics, Proto-Oncogene Protein c-ets-2 deficiency, Proto-Oncogene Protein c-ets-2 metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Fibroblasts metabolism, Neoplasms, Glandular and Epithelial metabolism, Neoplasms, Glandular and Epithelial pathology, PTEN Phosphohydrolase metabolism, Stromal Cells metabolism
- Abstract
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.
- Published
- 2009
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