title: Expression of regulators of mitotic fidelity are associated with intercellular heterogeneity and chromosomal instability in primary breast cancer.
abstract: Regulators of transition through mitosis such as SURVIVIN and Aurora kinase A (AURKA) have been previously implicated in the initiation of chromosomal instability (CIN), a driver of intratumour heterogeneity. We investigate the relationship between protein expression of these genes and directly quantified CIN, and their prognostic utility in breast cancer. The expression of SURVIVIN and AURKA was determined by immunohistochemistry in a cohort of 426 patients with primary breast cancer. The association between protein expression and histopathological characteristics, clinical outcome and CIN status, as determined by centromeric FISH and defined by modal centromere deviation, was analysed. Significantly poorer clinical outcome was observed in patients with high AURKA expression levels. Expression of SURVIVIN was elevated in ER-negative relative to ER-positive breast cancer. Both AURKA and SURVIVIN increased expression were significantly associated with breast cancer grade. There was a significant association between increased CIN and both increased AURKA and SURVIVIN expression. AURKA gene amplification was also associated with increased CIN. To our knowledge this is the largest study assessing CIN status in parallel with the expression of the mitotic regulators AURKA and SURVIVIN. These data suggest that elevated expression of AURKA and SURVIVIN, together with AURKA gene amplification, are associated with increased CIN in breast cancer, and may be used as a proxy for CIN in breast cancer samples in the absence of more advanced molecular measurements.
authors.affiliation: Cancer Research UK, London Research Institute, London, WC2A 3LY, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Roylance
authors.forename: David
authors.initials: D
authors.lastname: Endesfelder
authors.forename: Mariam
authors.initials: M
authors.lastname: Jamal-Hanjani
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Burrell
authors.forename: Patricia
authors.initials: P
authors.lastname: Gorman
authors.forename: Jil
authors.initials: J
authors.lastname: Sander
authors.forename: Niamh
authors.initials: N
authors.lastname: Murphy
authors.forename: Nicolai Juul
authors.initials: NJ
authors.lastname: Birkbak
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hanby
authors.forename: Valerie
authors.initials: V
authors.lastname: Speirs
authors.forename: Stephen R D
authors.initials: SR
authors.lastname: Johnston
authors.forename: Maik
authors.initials: M
authors.lastname: Kschischo
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D064096:Aurora Kinase A / Q000032:analysis* / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D043171:Chromosomal Instability; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008938:Mitosis / Q000235:genetics; D000077022:Survivin; D046888:Tissue Array Analysis
chemical_list: C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; C576917:AURKA protein, human; D064096:Aurora Kinase A