title: Overexpression of HIF1α and CAXI predicts poor outcome in early-stage triple negative breast cancer.
abstract: Dysregulated energy metabolism is one of the main mechanisms for uncontrolled growth in solid tumors. Hypoxia-inducible factor 1-alpha (HIF1α) is a transcription factor implicated in regulating several genes that are responsible for cell metabolism, including carbonic anhydrase IX (CAIX). The aim of this study is to determine the clinical significance of immunohistochemical metabolic alteration in early-stage triple negative breast cancer (TNBC) patients who received cyclophosphamide-based chemotherapy or radiotherapy and those with basal phenotype. Immunohistochemical staining for HIF1α and CAIX was performed to determine the correlation with clinicopathologic variables and survival outcome on tissue microarrays from 270 early-stage TNBC patients. In vitro experiments with multiple human TNBC cell lines, suppression of HIF1α by small interfering RNA (siRNA) significantly reduced CAIX protein expression in all cell lines. In multivariate analyses for different therapeutic modalities and basal phenotype, combined HIF1α and CAIX protein overexpression was significantly associated with disease-free survival in the total cohort (OR = 2.583, P = 0.002), stratified cohorts expressing basal phenotype (OR = 2.234, P = 0.021), and in those patients who received adjuvant chemotherapy (OR = 3.078, P = 0.023) and adjuvant radiotherapy (OR = 2.111, P = 0.050), respectively. In early TNBC, combined HIF1α and CAIX protein expression may serve as an unfavorable prognostic indicator particularly in patients treated with cyclophosphamide-based chemotherapy or radiotherapy as well as those with basal phenotype of breast cancer.
authors.affiliation: Department of Pathology, Bucheon St. Mary's Hospital, Catholic University, Gyeonggi-do, South Korea.
authors.forename: Min-Sun
authors.initials: MS
authors.lastname: Jin
authors.affiliation: Department of Radiation Oncology, Kangbuk Samsung Medical Center, Seoul, South Korea.
authors.forename: Hyebin
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul, South Korea.
authors.forename: In Ae
authors.initials: IA
authors.lastname: Park
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Yul Ri
authors.initials: YR
authors.lastname: Chung
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Kyung-Hun
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Surgery, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Hyeong-Gon
authors.initials: HG
authors.lastname: Moon
authors.affiliation: Department of Surgery, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Wonshik
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Radiation Oncology, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Kyubo
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Department of Surgery, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Noh
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul, South Korea. karlnash@naver.com.
authors.forename: Han Suk
authors.initials: HS
authors.lastname: Ryu
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000032:analysis; D000071231:Carbonic Anhydrase IX / Q000235:genetics*; D002256:Carbonic Anhydrases / Q000378:metabolism; D018572:Disease-Free Survival; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases
keywords: Adjuvant chemotherapy; Adjuvant radiotherapy; Basal phenotype; Cancer metabolism; Poor prognosis; Triple negative breast cancer