Pten in stromal fibroblasts suppresses mammary epithelial tumours

Anthony J. Trimboli, Carmen Z. Cantemir-Stone, Fu Li, Julie A. Wallace, Anand Merchant, Nicholas Creasap, John C. Thompson, Enrico Caserta, Hui Wang, Jean-Leon Chong, Shan Naidu, Guo Wei, Sudarshana M. Sharma, Julie A. Stephens, Soledad A. Fernandez, Metin N. Gurcan, Michael B. Weinstein, Sanford H. Barsky, Lisa Yee, Thomas J. Rosol, Paul C. Stromberg, Michael L. Robinson, Francois Pepin, Michael Hallett, Morag Park, Michael C. Ostrowski () and Gustavo Leone ()
Additional contact information
Anthony J. Trimboli: College of Biological Sciences
Carmen Z. Cantemir-Stone: College of Medicine
Fu Li: College of Biological Sciences
Julie A. Wallace: College of Medicine
Anand Merchant: College of Medicine
Nicholas Creasap: College of Biological Sciences
John C. Thompson: College of Biological Sciences
Enrico Caserta: College of Biological Sciences
Hui Wang: College of Biological Sciences
Jean-Leon Chong: College of Biological Sciences
Shan Naidu: College of Biological Sciences
Guo Wei: College of Biological Sciences
Sudarshana M. Sharma: College of Medicine
Julie A. Stephens: Center for Biostatistics, Office of Health Sciences,
Soledad A. Fernandez: Center for Biostatistics, Office of Health Sciences,
Metin N. Gurcan: Department of Biomedical Informatics,
Michael B. Weinstein: College of Biological Sciences
Sanford H. Barsky: Department of Pathology and,
Lisa Yee: School of Medicine, The Ohio State University, Columbus, Ohio 43210, USA
Thomas J. Rosol: College of Veterinary Medicine
Paul C. Stromberg: College of Veterinary Medicine
Michael L. Robinson: Center for Molecular and Human Genetics, Columbus Children’s Research Institute, Columbus, Ohio 43205, USA
Francois Pepin: Rosalind and Morris Goodman Cancer Center
Michael Hallett: Rosalind and Morris Goodman Cancer Center
Morag Park: Rosalind and Morris Goodman Cancer Center
Michael C. Ostrowski: College of Medicine
Gustavo Leone: College of Biological Sciences

Nature, 2009, vol. 461, issue 7267, 1084-1091

Abstract: 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.

Date: 2009
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DOI: 10.1038/nature08486

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