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B-Raf deficiency impairs tumor initiation and progression in a murine breast cancer model

Oncogene volume 38, pages 1324–1339 (2019)Cite this article

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Abstract

Copy number gains, point mutations and epigenetic silencing events are increasingly observed in genes encoding elements of the Ras/Raf/MEK/ERK signaling axis in human breast cancer. The three Raf kinases A-Raf, B-Raf, and Raf-1 have an important role as gatekeepers in ERK pathway activation and are often dysregulated by somatic alterations of their genes or by the aberrant activity of receptor tyrosine kinases (RTKs) and Ras-GTPases. B-Raf represents the most potent Raf isoform and a critical effector downstream of RTKs and RAS proteins. Aberrant RTK signaling is mimicked by the polyoma middle T antigen (PyMT), which activates various oncogenic signaling pathways, incl. the RAS/ERK axis, in a similar manner as RTKs in human breast cancer. Mammary epithelial cell directed expression of PyMT in mice by the MMTV-PyMT transgene induces mammary hyperplasia progressing over adenoma to metastatic breast cancer with an almost complete penetrance. To understand the functional role of B-Raf in this model for luminal type B breast cancer, we crossed MMTV-PyMT mice with animals that either lack B-Raf expression in the mammary gland or express the signaling impaired B-RafAVKA mutant. The AVKA mutation prevents phosphorylation of T599 and S602 in the B-Raf activation loop and thereby activation of the kinase by upstream signals. We demonstrate for the first time that B-Raf expression and activation is important for tumor initiation in vivo as well as for lung metastasis. Isogenic tumor cell lines generated from conditional Braf knock-out or knock-in mice displayed a reduction in EGF-induced ERK pathway activity as well as in proliferation and invasive growth in three-dimensional matrigel cultures. Our results suggest that B-Raf, which has been hardly studied in the context of breast cancer, represents a critical effector of the PyMT oncoprotein and invite for an assessment of its functional role in human breast cancer.

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Acknowledgements

This work was funded by the Deutsche Forschungsgemeinschaft (DFG) via the Collaborative Research Centre 850 (projects B4; B7, and C6), the Excellence Initiative of the German Federal and State Governments (EXC 294 BIOSS), the German Cancer Consortium (DKTK, L627) and the Spemann Graduate School for Biology and Medicine (GSC-4; SGBM) via fellowships to MK, SH, NK, CK. and NR. TB was also supported by the Emmy-Noether and Heisenberg programs of the DFG. We would also like to thank Chris Ormandy for helpful discussions, Ricarda Herr for advice, and Nicole Klemm and Ulrike Reif for expert technical assistance.

Author contributions

MK, TR, and TB designed and conceived experiments, conducted data interpretation and wrote the manuscript. MK, SE, SH, ML, UB, NR, SC, CS, FMU, NK, KR, and SB performed experimental work and data interpretation. CP and RZ contributed to experimental design and data interpretation. TR and TB supervised research and project planning.

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  1. These authors contributed equally: Thomas Reinheckel, Tilman Brummer

Authors and Affiliations

  1. Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Martin Köhler, Sophia Ehrenfeld, Sebastian Halbach, Manuel Lauinger, Ulrike Burk, Nadine Reischmann, Shuofei Cheng, Corinna Spohr, Kathrin Ringwald, Sandra Braun, Christoph Peters, Thomas Reinheckel & Tilman Brummer

  2. Spemann Graduate School for Biology and Medicine, University of Freiburg, Freiburg, Germany

    Martin Köhler, Sebastian Halbach, Nadine Reischmann, Corinna Spohr & Natalie Köhler

  3. Faculty of Biology, University of Freiburg, Freiburg, Germany

    Martin Köhler, Sophia Ehrenfeld, Sebastian Halbach, Manuel Lauinger, Nadine Reischmann, Corinna Spohr, Franziska Maria Uhl, Natalie Köhler & Kathrin Ringwald

  4. German Consortium for Translational Cancer Research DKTK, Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Sophia Ehrenfeld, Manuel Lauinger, Christoph Peters, Robert Zeiser, Thomas Reinheckel & Tilman Brummer

  5. Centre for Biological Signalling Studies BIOSS, University of Freiburg, Freiburg, Germany

    Ulrike Burk, Christoph Peters, Robert Zeiser, Thomas Reinheckel & Tilman Brummer

  6. Department of Hematology and Oncology, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Franziska Maria Uhl, Natalie Köhler & Robert Zeiser

  7. Comprehensive Cancer Centre Freiburg, Freiburg, Germany

    Christoph Peters, Robert Zeiser, Thomas Reinheckel & Tilman Brummer

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  1. Martin Köhler
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Köhler, M., Ehrenfeld, S., Halbach, S. et al. B-Raf deficiency impairs tumor initiation and progression in a murine breast cancer model. Oncogene 38, 1324–1339 (2019). https://doi.org/10.1038/s41388-018-0663-8

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