title: High IKKα expression is associated with reduced time to recurrence and cancer specific survival in oestrogen receptor (ER)-positive breast cancer.
abstract: The aim of our study was to examine the relationship between tumour IKKα expression and breast cancer recurrence and survival. Immunohistochemistry was employed in a discovery and a validation tissue microarray to assess the association of tumour IKKα expression and clinico-pathological characteristics. After siRNA-mediated silencing of IKKα, cell viability and apoptosis were assessed in MCF7 and MDA-MB-231 breast cancer cells. In both the discovery and validation cohorts, associations observed between IKKα and clinical outcome measures were potentiated in oestrogen receptor (ER) positive Luminal A tumours. In the discovery cohort, cytoplasmic IKKα was associated with disease-free survival (p = 0.029) and recurrence-free survival on tamoxifen (p < 0.001) in Luminal A tumours. Nuclear IKKα and a combination of cytoplasmic and nuclear IKKα (total tumour cell IKKα) were associated with cancer-specific survival (p = 0.012 and p = 0.007, respectively) and recurrence-free survival on tamoxifen (p = 0.013 and p < 0.001, respectively) in Luminal A tumours. In the validation cohort, cytoplasmic IKKα was associated with cancer-specific survival (p = 0.023), disease-free survival (p = 0.002) and recurrence-free survival on tamoxifen (p = 0.009) in Luminal A tumours. Parallel experiment with breast cancer cells in vitro demonstrated the non-canonical NF-κB pathway was inducible by exposure to lymphotoxin in ER-positive MCF7 cells and not in ER-negative MDA-MB-231 cells. Reduction in IKKα expression by siRNA transfection increased levels of apoptosis and reduced cell viability in MCF7 but not in MDA-MB-231 cells. IKKα is an important determinant of poor outcome in patients with ER-positive invasive ductal breast cancer and thus may represent a potential therapeutic target.
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Bennett
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Jean
authors.initials: J
authors.lastname: Quinn
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Pamela
authors.initials: P
authors.lastname: McCall
authors.affiliation: Department of Pathology, Southern General Hospital, Glasgow, Scotland, United Kingdom.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mallon
authors.affiliation: Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Glasgow, Scotland, United Kingdom.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Horgan
authors.affiliation: Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Glasgow, Scotland, United Kingdom.
authors.forename: Donald C
authors.initials: DC
authors.lastname: McMillan
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Paul
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Edwards
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007150:Immunohistochemistry; D008024:Ligands; D061986:MCF-7 Cells; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D010634:Phenobarbital / Q000737:chemistry; D011379:Prognosis; D034741:RNA, Small Interfering / Q000378:metabolism; D012189:Retrospective Studies; D013629:Tamoxifen / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D008024:Ligands; D034741:RNA, Small Interfering; D013629:Tamoxifen; C496559:CHUK protein, human; D051550:I-kappa B Kinase; D010634:Phenobarbital
keywords: IKKα; breast cancer; non canonical NF-kB pathway; oestrogen receptor; recurrence on tamoxifen