title: Hypoxia-induced protein CAIX is associated with somatic loss of BRCA1 protein and pathway activity in triple negative breast cancer.
abstract: The purpose of this study is to explore the relationship between tumor hypoxia assessed by CA IX protein expression and loss of BRCA1 function in triple negative breast cancer (TNBC). Protein expression of CA IX and BRCA1 was evaluated by AQUA™ technology on two breast cancer cohorts: an unselected cohort of 637 breast cancer patients and a TNBC cohort of 120 patients. Transcriptional profiling was performed on FFPE samples from the TNBC cohort to evaluate a gene expression signature associated with BRCA1 mutation (van't Veer et al., Nature 415(6871):530-536, 2002). CA IX is expressed in 7 % of the unselected breast cancer cohort and in 25 % of the TNBCs and is significantly associated with the triple negative phenotype. CA IX protein expression and BRCA1 protein expression are inversely correlated in both cohorts. Patients expressing high levels of CA IX show significantly worse overall survival (p = 0.02). Importantly, high CA IX protein expression occurs in patients who show the BRCA1 mutant signature and low levels of BRCA1 protein. These data suggest that elevated CA IX protein in TNBC is associated with a BRCA1 mutant signature and loss of BRCA1 function. CA IX may be a useful biomarker to identify triple negative patients with defective homologous recombination, who might benefit from PARP inhibitor therapy.
authors.affiliation: School of Medicine, Yale University, 310 Cedar Street, New Haven, CT 06520, USA. veronique.neumeister@yale.edu
authors.forename: Veronique M
authors.initials: VM
authors.lastname: Neumeister
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sullivan
authors.forename: Robert
authors.initials: R
authors.lastname: Lindner
authors.forename: Kimberley
authors.initials: K
authors.lastname: Lezon-Geyda
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Jan
authors.initials: J
authors.lastname: Zavada
authors.forename: Maritza
authors.initials: M
authors.lastname: Martel
authors.forename: Peter M
authors.initials: PM
authors.lastname: Glazer
authors.forename: David P
authors.initials: DP
authors.lastname: Tuck
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Lyndsay
authors.initials: L
authors.lastname: Harris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000951:Antigens, Neoplasm; D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C492913:BRCA1 protein, human; C508053:ERBB2 protein, human; C089226:CA9 protein, human