Letter | Published:

PIK3CAH1047R induces multipotency and multi-lineage mammary tumours

Nature volume 525, pages 114118 (03 September 2015) | Download Citation

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Abstract

The adult mouse mammary epithelium contains self-sustained cell lineages that form the inner luminal and outer basal cell layers, with stem and progenitor cells contributing to its proliferative and regenerative potential1,2,3,4. A key issue in breast cancer biology is the effect of genomic lesions in specific mammary cell lineages on tumour heterogeneity and progression. The impact of transforming events on fate conversion in cancer cells of origin and thus their contribution to tumour heterogeneity remains largely elusive. Using in situ genetic lineage tracing and limiting dilution transplantation, we have unravelled the potential of PIK3CAH1047R, one of the most frequent mutations occurring in human breast cancer5, to induce multipotency during tumorigenesis in the mammary gland. Here we show that expression of PIK3CAH1047R in lineage-committed basal Lgr5-positive and luminal keratin-8-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multi-lineage mammary tumours. Moreover, we show that the tumour cell of origin influences the frequency of malignant mammary tumours. Our results define a key effect of PIK3CAH1047R on mammary cell fate in the pre-neoplastic mammary gland and show that the cell of origin of PIK3CAH1047R tumours dictates their malignancy, thus revealing a mechanism underlying tumour heterogeneity and aggressiveness.

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Change history

  • 02 September 2015

    The spelling of author J.P.C. was corrected.

Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data sets generated for this study have been deposited in the Gene Expression Omnibus under accession numbers GSE59870, GSE59872 and GSE65411.

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Acknowledgements

The authors thank R. Thierry for help with image processing and quantification, S. Bichet and A. Bogucki for assistance with immunohistochemical staining, S. Thiry for assistance with the microarray analysis, L. Gelman, S. Bourke and M. Kirschmann for help with microscopy, C. Blanpain, B. Roska, B. Kinzel, J. Tchorz and A. Isken for providing mouse lines, and members of the Bentires-Alj group for their feedback. O.A. and R.D.C. were supported by National Cancer Institute grant U01 CA141582. Research in the laboratory of M.B.-A. is supported by the Novartis Research Foundation, the European Research Council (ERC starting grant 243211-PTPsBDC), the Swiss Cancer League, the Swiss National Foundation, and the Krebsliga Beider Basel.

Author information

Affiliations

  1. Friedrich Miescher Institute for Biomedical Research (FMI), 4058 Basel, Switzerland

    • Shany Koren
    • , Linsey Reavie
    • , Joana Pinto Couto
    • , Duvini De Silva
    • , Michael B. Stadler
    • , Tim Roloff
    • , Adrian Britschgi
    • , Tobias Eichlisberger
    • , Hubertus Kohler
    •  & Mohamed Bentires-Alj
  2. Swiss Institute of Bioinformatics, 4058 Basel, Switzerland

    • Michael B. Stadler
  3. Department of Pathology, Center for Comparative Medicine, University of California Davis, Davis, California 95616, USA

    • Olulanu Aina
    •  & Robert D. Cardiff

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Contributions

S.K. and M.B.-A. designed experiments, analysed the data and wrote the manuscript. L.R. contributed greatly to experimental design and data analysis. S.K. performed most of the experiments. L.R. and D.D.S. performed mammosphere cultures. L.R., D.D.S., J.P.C. and S.K. performed limiting dilution transplantations. M.B.S. and T.R. performed microarray data analysis. L.R. and J.P.C. quantified tumour immunohistochemistry. J.P.C. and A.B. isolated tumour RNA. A.B. performed immunoblotting. D.D.S. and T.E. provided technical assistance for several experiments. H.K. provided technical assistance for FACS experiments. O.A. and R.D.C. analysed histological tumour samples. All the authors discussed the data and participated in the preparation of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mohamed Bentires-Alj.

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DOI

https://doi.org/10.1038/nature14669

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