Lambe Institute for Translational ResearchNational University of Ireland Galway
XBP1 is a multitasking transcription factor and a key component of the unfolded protein response. Recently we have shown that NCOA3 is a transcriptional target of XBP1 and plays an important role in optimal activation of the PERK-ATF4 pathway thereby regulating tumour vascularity and invasion. Nuclear receptor coactivator 3 (NCOA3) is an oncogenic coactivator and interacts with nuclear receptors (NR) to enhance the expression of cognate target genes. Our results show that XBP1-mediates anti-estrogen resistance in part through regulating NCOA3. Increased expression of NCOA3 was associated with poor prognosis and higher levels of XBP1 in breast cancer tissues. Our results show that NCOA3 is required for induction of XBP1 during oestrogen stimulation and uncovers a positive feedback regulatory loop that maintains high levels of NCOA3 and XBP1 in breast cancer. Taken together our data identifies XBP1-NCOA3 axis that regulates cell fate decisions in ER-positive breast cancer cells. I hypothesize that XBP1-NCOA3 axis constitutes an important signalling node downstream of activated ERα and an attractive target for therapeutic intervention in ER-positive breast cancer. The main focus of my group is to elucidate how somatic mutations in the genes encoding components of oestrogen signalling regulate the activation and output of XBP1-NCOA3 axis. Additionally, we are evaluating the efficacy of XBP1 and NCOA3 targeting agents for preventing and/or reversing endocrine resistance in breast cancer.
GENE EXPRESSION PROFILES, LENTIVIRAL ShRNA, CRISPR-CAS9, CAM FOR ANGIOGENESIS, APOPTOSIS AND UPR
cell lines, TMAs, Cancer tissue and pheripheral blood for biomarker studies