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Oncogenic suppression of apoptosis uncovers a Rac1/JNK proliferation pathway activated by loss of Par3

Oncogene volume 34, pages 3199–3206 (2015)Cite this article

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Abstract

Disruption of epithelial organization and loss of growth control are universal features of carcinomas, yet how these features are linked during cancer progression remains poorly understood. Cell polarity proteins control cellular and tissue organization and are emerging as important mediators of cancer progression. The Par3 polarity protein is a molecular scaffold that functions to recruit and spatially organize signaling factors, and was recently identified as a suppressor of breast cancer invasion and metastasis. Here, we show that loss of Par3 in mammary epithelial cells promotes apoptosis, and that oncogenic Notch overcomes the apoptotic signal to reveal an unexpected pro-proliferative role for loss of Par3 in mammary tumors. In this context, loss of Par3 deregulates Rac1 activity to activate Jun N-terminal Kinase-dependent proliferation and tumor growth. Thus, we demonstrate a mechanism by which loss of Par3 promotes proliferation and tumorigenesis, which supports a tumor-suppressive function for Par3 in the mammary epithelium.

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Acknowledgements

We thank Didier Trono (Lausanne, Switzerland) for lentivectors. K8 hybridoma, developed by Philippe Brulet and Rolf Kemler, was obtained from the Universtiy of Iowa Developmental Hybridoma Bank. This work was supported by grants from TFRI (Project #1009) and CIHR (MOP-119482) to LM. LM is a FRQS Research Scholar.

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Authors and Affiliations

  1. Department of Oncology, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada

    A Archibald, C Mihai & L McCaffrey

  2. Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville,, TN, USA

    I G Macara

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  1. A Archibald
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  2. C Mihai
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  3. I G Macara
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  4. L McCaffrey
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Correspondence to L McCaffrey.

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Archibald, A., Mihai, C., Macara, I. et al. Oncogenic suppression of apoptosis uncovers a Rac1/JNK proliferation pathway activated by loss of Par3. Oncogene 34, 3199–3206 (2015). https://doi.org/10.1038/onc.2014.242

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