Regulation of the interferon-gamma (IFN-γ) pathway by p63 and Δ133p53 isoform in different breast cancer subtypes

// Sunali Y. Mehta 1, 2 , Brianna C. Morten 4 , Jisha Antony 1, 2 , Luke Henderson 1 , Annette Lasham 2, 3 , Hamish Campbell 5 , Heather Cunliffe 1 , Julia A. Horsfield 1, 2 , Roger R. Reddel 5 , Kelly A. Avery-Kiejda 4 , Cristin G. Print 2, 3, * and Antony W. Braithwaite 1, 2, 5, * 1 Pathology Department, University of Otago, Dunedin, New Zealand 2 Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand 3 Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand 4 Priority Research Centre for Cancer Research, Innovation and Translation, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Calvary Mater Hospital, Waratah NSW, Australia 5 Children’s Medical Research Institute, The University of Sydney, Westmead, NSW, Australia * These authors have contributed equally to the work Correspondence to: Antony W. Braithwaite, email: antony.braithwaite@otago.ac.nz Keywords: TP53; TP63; isoforms; immune response; breast cancer Received: May 22, 2018      Accepted: May 31, 2018      Published: June 26, 2018 ABSTRACT The TP53 family consists of three sets of transcription factor genes, TP53 , TP63 and TP73 , each of which expresses multiple RNA variants and protein isoforms. Of these, TP53 is mutated in 25-30% of breast cancers. How TP53 mutations affect the interaction of TP53 family members and their isoforms in breast cancer is unknown. To investigate this, 3 independent breast cancer cohorts were stratified into 4 groups based on oestrogen receptor (ER) and TP53 mutation status. Using bioinformatic methodologies, principal signalling pathways associated with the expression of TP53 family members were identified. Results show an enrichment of IFN-γ signalling associated with TP63 RNA in wild type TP53 (wt TP53 ), ER negative (ER-) tumours and with Δ133TP53 RNA in mutant TP53 (m TP53 ) ER positive (ER+) tumours. Moreover, tumours with low IFN-γ signalling were associated with significantly poorer patient outcome. The predicted changes in expression of a subset of RNAs involved in IFN-γ signalling were confirmed in vitro . Our data show that different members of the TP53 family can drive transcription of genes involved in IFN-γ signalling in different breast cancer subgroups.