title: The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy.
abstract: Basal-like tumours account for 15% of invasive breast carcinomas and are associated with a poorer prognosis and resistance to therapy. We hypothesised that this aggressive phenotype is because of an intrinsically elevated hypoxic response. Microarrayed tumours from 188 patients were stained for hypoxia-inducible factor (HIF)-1alpha, prolyl hydroxylase (PHD)1, PHD2, PHD3 and factor inhibiting HIF (FIH)-1, and carbonic anhydrase (CA) IX stained in 456 breast tumours. Tumour subtypes were correlated with standard clincopathological parameters as well as hypoxic markers. Out of 456 tumours 62 (14%) tumours were basal-like. These tumours were positively correlated with high tumour grade (P<0.001) and were associated with a significantly worse disease-free survival compared with luminal tumours (P<0.001). Fifty percent of basal-like tumours expressed HIF-1alpha, and more than half expressed at least one of the PHD enzymes and FIH-1. Basal-like tumours were nine times more likely to be associated with CAIX expression (P<0.001) in a multivariate analysis. Carbonic anhydrase IX expression was positively correlated with tumour size (P=0.005), tumour grade (P<0.001) and oestrogen receptor (ER) negativity (P<0.001). Patients with any CAIX-positive breast tumour phenotype and in the basal tumour group had a significantly worse prognosis than CAIX-negative tumours when treated with chemotherapy (P<0.001 and P=0.03, respectively). The association between basal phenotype and CAIX suggests that the more aggressive behaviour of these tumours is partly due to an enhanced hypoxic response. Further, the association with chemoresistance in CAIX-positive breast tumours and basal-like tumours in particular raises the possibility that targeted therapy against HIF pathway or downstream genes such as CAs may be an approach to investigate for these patients.
authors.affiliation: Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, UK.
authors.forename: E Y
authors.initials: EY
authors.lastname: Tan
authors.forename: M
authors.initials: M
authors.lastname: Yan
authors.forename: L
authors.initials: L
authors.lastname: Campo
authors.forename: C
authors.initials: C
authors.lastname: Han
authors.forename: E
authors.initials: E
authors.lastname: Takano
authors.forename: H
authors.initials: H
authors.lastname: Turley
authors.forename: I
authors.initials: I
authors.lastname: Candiloro
authors.forename: F
authors.initials: F
authors.lastname: Pezzella
authors.forename: K C
authors.initials: KC
authors.lastname: Gatter
authors.forename: E K A
authors.initials: EK
authors.lastname: Millar
authors.forename: S A
authors.initials: SA
authors.lastname: O'Toole
authors.forename: C M
authors.initials: CM
authors.lastname: McNeil
authors.forename: P
authors.initials: P
authors.lastname: Crea
authors.forename: D
authors.initials: D
authors.lastname: Segara
authors.forename: R L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.forename: S B
authors.initials: SB
authors.lastname: Fox
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D049308:Dioxygenases / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D006899:Mixed Function Oxygenases; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011379:Prognosis; D012097:Repressor Proteins / Q000378:metabolism; D015996:Survival Rate; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C430869:PHF12 protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; D006899:Mixed Function Oxygenases; D049308:Dioxygenases; C439790:HIF1AN protein, human; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases