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Unravelling the Unfolded Protein Response in Cancer Progression
Ongoing Research by the Gupta Group (Email: firstname.lastname@example.org)
Research Focus 1: Unfolded protein response in cancer: regulation by microRNAs
The stressful conditions in the tumour microenvironment including low oxygen supply, nutrient deprivation and pH changes activate a range of cellular stress-response pathways. Tumour hypoxia is a common microenvironmental factor that adversely influences tumour phenotype and treatment response. Cellular adaptation to hypoxia occurs through multiple mechanisms, including activation of the unfolded protein response (UPR). UPR attempts to restore ER homeostasis by increasing ER bio-genesis, decreasing the influx of new proteins into the ER, promoting the transport of damaged proteins from the ER to the cytosol for degradation, and upregulating protein folding chaperones. Although the unfolded protein response is primarily a pro-survival response, in the event of prolonged or severe ER stress that is not resolved, the unfolded protein response switches to initiation of apoptosis. The molecular mechanisms involved in the transition of the UPR from a protective to an apoptotic phase are unclear.
MicroRNAs (miRNAs) have been shown to be critically involved in control of cell survival and cell death decisions. The main function of miRNAs is to direct posttranscriptional regulation of gene expression, typically by binding to 3’ UTR of cognate mRNAs and inhibiting their translation and/or stability. Global downregulation of miRNAs is a common feature of human tumours. Loss of miRNA biogenesis has been shown to enhance cancer progression. Further several components of miRNA biogenesis machinery (XPO5, DICER and TRBP) have been shown to act as haploinsufficient tumour suppressors. How the dysregulation of miRNA biogenesis promotes tumour development is not clearly understood. The main focus of research in my group is to evaluate the role of microRNAs in determining cell fate during conditions of ER stress. We use a combination of molecular cell biology, transcriptomics, proteomics and miRNA expression profiling to address specific questions such as:
(i) What is the role of miRNAs in ER stress-induced apoptosis?
(ii) Does impaired miRNA biogenesis contribute to cancer progression by inhibiting ER stress-induced apoptosis?
Research Focus 2: Role of IRE1-XBP1 axis in endocrine resistance in ER-positive breast cancer
Invasive breast cancer (IBC) is a heterogeneous disease with varied molecular features, behaviour, and response to therapy. Over the past decade, transcriptome-wide studies of patients with IBC have lead to the identification of clinically relevant subtypes: luminal A, luminal B, HER2-overexpressing, basal-like and normal breast tissue-like. The Cancer Genome Atlas (TCGA) consortium recently reported that most dominant feature of Luminal/ER-positive breast cancers is increased mRNA and protein levels of ESR1, GATA3, FOXA1, XBP1 and MYB. Recent studies indicate a crucial role for the IRE1/XBP1 pathway in several aspects of ER-positive breast cancer (Figure 1). XBP1 is transcriptionally induced during estrogen stimulation and XBP1s protein expression is upregulated following estradiol (E2) treatment of ER-positive human breast cancer cell lines. XBP1 physically interacts with ER and potentiate ER-dependent transcriptional activity in a ligand-independent manner. Ectopic expression of XBP1s in ER-positive breast cancer cells can lead to estrogen-independent growth and reduced sensitivity to anti-estrogens. Expression of XBP1s is significantly associated with clinical outcome of endocrine-treated breast cancer. We are taking a multidisciplinary approach to elucidate the role of the IRE1-XBP1 in regulation of estrogen signalling underpinning anti-estrogen resistance in breast cancer. The central questions are:
(i) How estrogen signalling intersects with the UPRosome to regulate its activation?
(ii) What is the transcriptional network of XBP1s in the context of estrogen signalling?
(iii) What is the therapeutic and prognostic value of IRE1-XBP1 axis in ER-positive breast cancer?
Post doctoral fellows
Undergraduate research project students
Darren Kilmartin (PathSoc summer research fellowship)
Alice Deane (BSc Physiology 4th year project)
John O’Dea (BSc Physiology 4th year project)
Kieran McMullan (HRB summer research fellowship)
Eamonn McCrave (College of Medicine summer research fellowship)
Rachel Nolan (BSc Pharmacology 4th year project)
• For a list of Dr. Sanjeev Gupta’s publications, please click here: