Abstract
Despite the progress made in targeted anticancer therapies in recent years, challenges remain. The identification of new potential targets will ensure that the arsenal of cancer therapies continues to expand. FAM83B was recently discovered in a forward genetic screen for novel oncogenes that drive human mammary epithelial cell (HMEC) transformation. We report here that elevated FAM83B expression increases Phospholipase D (PLD) activity, and that suppression of PLD1 activity prevents FAM83B-mediated transformation. The increased PLD activity is engaged by hyperactivation of epidermal growth factor receptor (EGFR), which is regulated by an interaction involving FAM83B and EGFR. Preventing the FAM83B/EGFR interaction by site-directed mutation of lysine 230 of FAM83B suppressed PLD activity and MAPK signaling. Furthermore, ablation of FAM83B expression from breast cancer cells inhibited EGFR phosphorylation and suppressed cell proliferation. We propose that understanding the mechanism of FAM83B-mediated transformation will provide a foundation for future therapies aimed at targeting its function as an intermediary in EGFR, MAPK and mTOR activation.
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Acknowledgements
We are grateful to Chase Foy for technical help and Damian Junk for helpful discussions. The core facilities provided by the Case Comprehensive Cancer Center (P30 CA43703; Athymic Animal and Xenograft Core Facility; Gene Expression and Genotyping Core Facility; Cytometry and Imaging Microscopy Core Facility; Radiation Resources Core Facility). This work was supported by the US National Institutes of Health (R01CA138421 to MWJ; T32CA059366 to RC and CB), the Department of Defense Breast Cancer Research Program (BC095847 and BC074072 to MWJ), the American Cancer Society (RSG-10-072-01-TBG to MWJ) and the McDonnell Foundation for brain cancer research (HAB) and the NIH MLPCN U54 MH084659 (CWL) Vanderbilt Specialized Chemistry Center for Accelerated Probe Development.
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Dr Jackson's work has been funded by the NIH, the American Cancer Society, and the Department of Defense. Dr H Alex Brown's work has been funded by the McDonnell Foundation. Dr Cipriano's and Ms Bartel's work has been funded by the NIH. The remaining authors declare no conflict of interest.
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Cipriano, R., Bryson, B., Miskimen, K. et al. Hyperactivation of EGFR and downstream effector phospholipase D1 by oncogenic FAM83B. Oncogene 33, 3298–3306 (2014). https://doi.org/10.1038/onc.2013.293
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DOI: https://doi.org/10.1038/onc.2013.293
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