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PKA signaling drives mammary tumorigenesis through Src

Oncogene volume 34, pages 1160–1173 (2015)Cite this article

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Abstract

Protein kinase A (PKA) hyperactivation causes hereditary endocrine neoplasias; however, its role in sporadic epithelial cancers is unknown. Here, we show that heightened PKA activity in the mammary epithelium generates tumors. Mammary-restricted biallelic ablation of Prkar1a, which encodes for the critical type-I PKA regulatory subunit, induced spontaneous breast tumors characterized by enhanced type-II PKA activity. Downstream of this, Src phosphorylation occurs at residues serine-17 and tyrosine-416 and mammary cell transformation is driven through a mechanism involving Src signaling. The phenotypic consequences of these alterations consisted of increased cell proliferation and, accordingly, expansion of both luminal and basal epithelial cell populations. In human breast cancer, low PRKAR1A/high SRC expression defines basal-like and HER2 breast tumors associated with poor clinical outcome. Together, the results of this study define a novel molecular mechanism altered in breast carcinogenesis and highlight the potential strategy of inhibiting SRC signaling in treating this cancer subtype in humans.

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Acknowledgements

We thank Megan K Barker and Paul Waterhouse for critical reading of the manuscript. We would also like to acknowledge Shareen Ezzat for sharing the small molecule Dasatinib, Vuk Stambolic for offering insight into biochemistry experiments and the IDIBELL’s Biostatistics Unit for help in analyzing breast cancer data sets. This work was supported by a Canadian Breast Cancer Foundation (CBCF) grant to RK and the Spanish Ministry of Health grant FIS-PI12/01528 and RD12/0036/0008 to MAP. AGB holds a CBCF fellowship.

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Authors and Affiliations

  1. Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada,

    A G Beristain, S D Molyneux, P A Joshi, N C Pomroy, M A Di Grappa & R Khokha

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada,

    S D Molyneux, P A Joshi, G G Privé & R Khokha

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    M C Chang & R Khokha

  4. Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, OH, USA

    L S Kirschner

  5. Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain

    M A Pujana

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  1. A G Beristain
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Correspondence to R Khokha.

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Beristain, A., Molyneux, S., Joshi, P. et al. PKA signaling drives mammary tumorigenesis through Src. Oncogene 34, 1160–1173 (2015). https://doi.org/10.1038/onc.2014.41

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