title: Thromboxane A2 receptor (TBXA2R) is a potent survival factor for triple negative breast cancers (TNBCs).
abstract: Triple Negative Breast Cancer (TNBC) is defined by the lack of ERα, PR expression and HER2 overexpression and is the breast cancer subtype with the poorest clinical outcomes. Our aim was to identify genes driving TNBC proliferation and/or survival which could represent novel therapeutic targets.We performed microarray profiling of primary TNBCs and generated differential genelists based on clinical outcomes following the chemotherapy regimen FEC (5-Fluorouracil/Epirubicin/Cyclophosphamide -'good' outcome no relapse > 3 years; 'poor' outcome relapse < 3 years). Elevated expression of thromboxane A2 receptor (TBXA2R) was observed in 'good' outcome TNBCs. TBXA2R expression was higher specifically in TNBC cell lines and TBXA2R knockdowns consistently showed dramatic cell killing in TNBC cells. TBXA2R mRNA and promoter activities were up-regulated following BRCA1 knockdown, with c-Myc being required for BRCA1-mediated transcriptional repression.We demonstrated that TBXA2R enhanced TNBC cell migration, invasion and activated Rho signalling, phenotypes which could be reversed using Rho-associated Kinase (ROCK) inhibitors. TBXA2R also protected TNBC cells from DNA damage by negatively regulating reactive oxygen species levels. In summary, TBXA2R is a novel breast cancer-associated gene required for the survival and migratory behaviour of a subset of TNBCs and could provide opportunities to develop novel, more effective treatments.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Katy
authors.initials: K
authors.lastname: Orr
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Niamh E
authors.initials: NE
authors.lastname: Buckley
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Paula
authors.initials: P
authors.lastname: Haddock
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: James
authors.affiliation: Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Parent
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: McQuaid
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Mullan
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D019398:Genes, BRCA1; D016259:Genes, myc; D006801:Humans; D009361:Neoplasm Invasiveness; D017382:Reactive Oxygen Species / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D064726:Triple Negative Breast Neoplasms / Q000401:mortality* / Q000473:pathology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D054460:rho-Associated Kinases
keywords: BRCA1; TBXA2R; TNBC; cell survival; predictive marker