Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers

Journal Reference

Oncogene. 2015 Jun 15 (Advance online publication).

Marques E¹, Englund JI¹, Tervonen TA¹, Virkunen E¹, Laakso M², Myllynen M¹, Mäkelä A¹, Ahvenainen M¹, Lepikhova T³, Monni O³, Hautaniemi S², Klefström J¹.

[expand title=”Show Affiliations”]

Cancer Cell Circuitry Laboratory, Research programs unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Finland.
Systems Biology Laboratory, Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

[/expand]

Abstract

Differentiated epithelial structure communicates with individual constituent epithelial cells to suppress their proliferation activity. However, the pathways linking epithelial structure to cessation of the cell proliferation machinery or to unscheduled proliferation in the context of tumorigenesis are not well defined. Here we demonstrate the strong impact of compromised epithelial integrity on normal and oncogenic Myc-driven proliferation in three-dimensional mammary epithelial organoid culture. Systematic silencing of 34 human homologs of Drosophila genes, with previously established functions in control of epithelial integrity, demonstrates a role for human genes of apico-basal polarity, Wnt and Hippo pathways and actin dynamics in regulation of the size, integrity and cell proliferation in organoids. Perturbation of these pathways leads to diverse functional interactions with Myc: manifested as a RhoA-dependent synthetic lethality and Par6-dependent effects on the cell cycle. Furthermore, we show a role for Par6G as a negative regulator of the phosphatidylinositol 3′-kinase/phosphoinositide-dependent protein kinase 1/Akt pathway and epithelial cell proliferation and evidence for frequent inactivation of Par6G gene in epithelial cancers. The findings demonstrate that determinants of epithelial structure regulate thecell proliferation activity via conserved and cancer-relevant regulatory circuitries, which are important for epithelial cell cycle restriction and may provide new targets for therapeutic intervention.

Go To Oncogene.

About the author

Juha Klefström, PhD, is a Research Director in Research Programs Unit, Medical Faculty, University of Helsinki and in Biomedicum Functional Genomics Unit. Klefström’s primary research interests are in breast cancer biology, genetically engineered mouse models of breast cancer, mammary gland reconstitution techniques, ex vivo organoid cultures and recombinant viral gene transfer methods. His laboratory has established variety of three-dimensional culture systems for primary mammary epithelial and tumor organoids to explore roles and targetability of Myc, Lkb1 and cell polarity pathways in breast cancer

About the author

Elsa Marques, MSc, is a PhD student in Research Programs Unit/ Translational Cancer Biology, University of Helsinki. She graduated from University of Coimbra, Portugal and followed her interests in cancer biology to Finland where she joined the laboratory of Juha Klefström. Her current main research interests are in the role of apicobasal polarity genes in development of breast cancer.