title: PKA signaling drives mammary tumorigenesis through Src.
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.
authors.affiliation: Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: A G
authors.initials: AG
authors.lastname: Beristain
authors.affiliation: 1] Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: S D
authors.initials: SD
authors.lastname: Molyneux
authors.affiliation: 1] Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: P A
authors.initials: PA
authors.lastname: Joshi
authors.affiliation: Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: N C
authors.initials: NC
authors.lastname: Pomroy
authors.affiliation: Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: Di Grappa
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M C
authors.initials: MC
authors.lastname: Chang
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, OH, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Kirschner
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: G G
authors.initials: GG
authors.lastname: Privé
authors.affiliation: Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Pujana
authors.affiliation: 1] Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Khokha
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics / Q000378:metabolism*; D000069439:Dasatinib; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D000077191:Wortmannin; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000730:Androstadienes; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517835:Prkar1a protein, mouse; D011743:Pyrimidines; D013844:Thiazoles; D019061:src-Family Kinases; D000069439:Dasatinib; D000077191:Wortmannin