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.

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Acknowledgements

We thank M. Rawahneh and J. Moffitt for histotechnical assistance, K. Kornacker, S. Cory and I. Vasudeva Murthy for bioinformatics assistance, P. Gulati for statistics assistance, the Ohio State University Human Tissue Resource Network and the Ohio State University Comprehensive Cancer Center Microarray, Nucleic Acids, Trangenics and Flow Cytometry Shared Facilities for technical assistance. MMTV-ErbB2 mice were provided by W. Muller. This work was funded by the National Institutes of Health to G.L. (R01CA85619, R01HD47470, P01CA097189) and to M.C.O. (R01CA053271, P01CA097189), by the Komen Breast Cancer Foundation and Evelyn Simmers Charitable Trust to M.C.O., by the Terry Fox New Frontiers Group Grant to M.P., and by the Natural Science and Engineering Research Council of Canada Discovery Grants Program grant to M.H. F.L. and F.P. were funded by Department of Defense Pre-doctoral Fellowships and J.-L.C. was funded by a Department of Defense Postdoctoral Fellowship. G.L. is the recipient of the Pew Charitable Trusts Scholar Award and the Leukemia and Lymphoma Society Scholar Award. M.P. holds the Diane and Sal Guerrera Chair in Cancer Genetics at McGill University.

Author Contributions G.L. and M.C.O. designed and supervised this study, analysed data, and helped write and edit the manuscript. A.J.T., C.Z.C., F.L. and J.A.W. designed and performed experiments, collected and analysed data, and co-wrote the paper. N.C., J.C.T., H.W., J-L.C., S.M.S. and M.N.G. technically assisted with experiments, and collected and analysed data. G.W., A.J.T., M.L.R and M.W performed experiments in initial stages of the project, particularly in designing and characterizing the mouse models. S.N., P.S. and T.J.R. contributed to the histopathological analysis of the mouse mammary tumour models and writing the manuscript. S.H.B. and L.Y. contributed to the histopathological analysis of human samples and writing the manuscript. S.A.F. and J.A.S. contributed to the statistical analyses of data and writing the manuscript. A.M., F.P., J.A.W., E.C., M.H. and M.P. contributed to the analysis and comparison of mouse and human microarray data and writing the mansucript.

Author information

Author notes

    • Anthony J. Trimboli
    • , Carmen Z. Cantemir-Stone
    •  & Fu Li

    These authors contributed equally to this work.

    • Sanford H. Barsky
    •  & Michael L. Robinson

    Present addresses: Department of Pathology, University of Nevada School of Medicine, Reno, Nevada 89557, and Nevada Cancer Institute, Las Vegas, Nevada 89135, USA (S.H.B.); Department of Zoology, Miami University, Oxford, Ohio 45056, USA (M.L.R.).

Affiliations

  1. Department of Molecular Genetics, College of Biological Sciences,

    • Anthony J. Trimboli
    • , Fu Li
    • , Nicholas Creasap
    • , John C. Thompson
    • , Enrico Caserta
    • , Hui Wang
    • , Jean-Leon Chong
    • , Shan Naidu
    • , Guo Wei
    • , Michael B. Weinstein
    •  & Gustavo Leone
  2. Department of Molecular Virology, Immunology and Medical Genetics,

    • Anthony J. Trimboli
    • , Nicholas Creasap
    • , John C. Thompson
    • , Enrico Caserta
    • , Hui Wang
    • , Jean-Leon Chong
    • , Shan Naidu
    • , Michael B. Weinstein
    •  & Gustavo Leone
  3. Department of Molecular and Cellular Biochemistry, College of Medicine,

    • Carmen Z. Cantemir-Stone
    • , Fu Li
    • , Julie A. Wallace
    • , Anand Merchant
    • , Guo Wei
    • , Sudarshana M. Sharma
    •  & Michael C. Ostrowski
  4. Department of Veterinary Biosciences, College of Veterinary Medicine,

    • Shan Naidu
    • , Thomas J. Rosol
    •  & Paul C. Stromberg
  5. Center for Biostatistics, Office of Health Sciences,

    • Julie A. Stephens
    •  & Soledad A. Fernandez
  6. Department of Biomedical Informatics,

    • Metin N. Gurcan
  7. Department of Pathology and,

    • Sanford H. Barsky
  8. Department of Surgery, School of Medicine, The Ohio State University, Columbus, Ohio 43210, USA

    • Lisa Yee
  9. Center for Molecular and Human Genetics, Columbus Children’s Research Institute, Columbus, Ohio 43205, USA

    • Michael L. Robinson
  10. Department of Biochemistry, Rosalind and Morris Goodman Cancer Center,

    • Francois Pepin
    • , Michael Hallett
    •  & Morag Park
  11. McGill Center for Bioinformatics,

    • Francois Pepin
    •  & Michael Hallett
  12. Department of Oncology, McGill University, Québec H3A 1A1, Canada

    • Morag Park
  13. Tumor Microenvironment Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA

    • Michael C. Ostrowski
    •  & Gustavo Leone

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https://doi.org/10.1038/nature08486

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