Journal Article

Pten in stromal fibroblasts suppresses mammary epithelial tumours

Fernandez, Soledad A., Creasap, Nicholas, Leone, Gustavo, Li, Fu, Robinson, Michael L., Pepin, Francois, Wei, Guo, Stephens, Julie A., Park, Morag, Trimboli, Anthony J., Naidu, Shan, Caserta, Enrico, Hallett, Michael, Merchant, Anand, Weinstein, Michael B., Sharma, Sudarshana M., Wang, Hui, Chong, Jean-Leon, Yee, Lisa, Thompson, John C., Ostrowski, Michael C., Wallace, Julie A., Cantemir-Stone, Carmen Z., Rosol, Thomas J., Barsky, Sanford H., Gurcan, Metin N., Stromberg, Paul C.

2009

Overview

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. Pten–Ets2 antitumour axis The tumour microenvironment plays an important role in tumorigenesis. Trimboli et al . now show that deletion of the tumour suppressor gene Pten in stromal fibroblasts leads to the development of mammary tumours of epithelial origin. Loss of Pten leads to extracellular matrix remodelling, infiltration of immune cells and enhanced angiogenesis. These effects are in part mediated by activation of the transcription factor Ets2 in stromal cells. Pten loss and associated changes in gene expression can also be observed in the stroma of human breast tumours. This work identifies the Pten–Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours. The tumour microenvironment has an important role in tumorigenesis. Here, the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands is shown to accelerate the initiation, progression and malignant transformation of mammary epithelial tumours. The data presented suggest that the Pten–Ets2 axis — Ets2 being a transcription factor activated by the loss of Pten — is a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Breast cancer / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cell cycle / Cell Line, Tumor / Cell Proliferation / Cell Transformation, Neoplastic / Development and progression / Epithelial tumors / Extracellular Matrix - metabolism / Fibroblasts / Fibroblasts - metabolism / Gene Deletion / Gene expression / Gene Expression Regulation, Neoplastic / Genetic aspects / Health aspects / Humanities and Social Sciences / Humans / Immunity, Innate / Inactivation / Kinases / Mammary Neoplasms, Experimental - metabolism / Mammary Neoplasms, Experimental - pathology / Mice / Mice, Transgenic / multidisciplinary / Neoplasms, Glandular and Epithelial - metabolism / Neoplasms, Glandular and Epithelial - pathology / Phosphatase / Physiological aspects / Prevention / Proto-Oncogene Protein c-ets-2 - deficiency / Proto-Oncogene Protein c-ets-2 - metabolism / PTEN Phosphohydrolase - deficiency / PTEN Phosphohydrolase - genetics / PTEN Phosphohydrolase - metabolism / Science / Science (multidisciplinary) / Stromal Cells - metabolism / Tumor suppressor genes / Tumors