title: Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential.
abstract: Breast cancer is the commonest form of cancer in women, but successful treatment is confounded by the heterogeneous nature of breast tumours: Effective treatments exist for hormone-sensitive tumours, but triple-negative breast cancer results in poor survival. An area of increasing interest is metabolic reprogramming, whereby drug-induced alterations in the metabolic landscape of a tumour slow tumour growth and/or increase sensitivity to existing therapeutics. Nuclear receptors are transcription factors central to the expression of metabolic and transport proteins, and thus represent potential targets for metabolic reprogramming. We show that activation of the nuclear receptor FXR, either by its endogenous ligand CDCA or the synthetic GW4064, leads to cell death in four breast cancer cell lines with distinct phenotypes: MCF-10A (normal), MCF-7 (receptor positive), MDA-MB-231 and MDA-MB-468 (triple negative). Furthermore, we show that the mechanism of cell death is predominantly through the intrinsic apoptotic pathway. Finally, we demonstrate that FXR agonists do not stimulate migration in breast cancer cell lines, an important potential adverse effect. Together, our data support the continued examination of FXR agonists as a novel class of therapeutics for the treatment of breast cancer.
authors.affiliation: School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK.
authors.forename: Noura
authors.initials: N
authors.lastname: Alasmael
authors.affiliation: School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK.
authors.forename: Rati
authors.initials: R
authors.lastname: Mohan
authors.affiliation: School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK.
authors.forename: Lisiane B
authors.initials: LB
authors.lastname: Meira
authors.affiliation: Clinical PD Biomarker Group, The Institute of Cancer Research, Sutton, SM2 5NG, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Swales
authors.affiliation: School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. Electronic address: n.plant@surrey.ac.uk.
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Plant
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064
keywords: Apoptosis; Autophagy; Bile acids; Nuclear receptor; Triple negative breast cancer