Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 2009 Oct 22;461(7267):1084-91
Date
10/23/2009Pubmed ID
19847259Pubmed Central ID
PMC2767301DOI
10.1038/nature08486Scopus ID
2-s2.0-70350510924 (requires institutional sign-in at Scopus site) 440 CitationsAbstract
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.
Author List
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, Leone GAuthors
Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of WisconsinAnthony 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
AnimalsBreast Neoplasms
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic
Extracellular Matrix
Fibroblasts
Gene Deletion
Gene Expression Regulation, Neoplastic
Humans
Immunity, Innate
Mammary Neoplasms, Experimental
Mice
Mice, Transgenic
Neoplasms, Glandular and Epithelial
PTEN Phosphohydrolase
Proto-Oncogene Protein c-ets-2
Stromal Cells