title: Expression of aldehyde dehydrogenase after neoadjuvant chemotherapy is associated with expression of hypoxia-inducible factors 1 and 2 alpha and predicts prognosis in locally advanced breast cancer.
abstract: OBJECTIVE
  To analyze the expression of hypoxia-inducible factors (hypoxia-inducible factor 1A and hypoxia-inducible factor 2A) and aldehyde dehydrogenase proteins in patients with locally advanced breast carcinoma who were subjected to neoadjuvant chemotherapy.
  
  
  METHODS
  We included 90 patients with histologically confirmed stage II and III breast carcinoma who were treated with neoadjuvant chemotherapy between 2000 and 2005. Immunohistochemistry for aldehyde dehydrogenase, hypoxia-inducible factor 1A, and hypoxia-inducible factor 2A was performed before and after neoadjuvant chemotherapy. We analyzed the influence of clinical and pathological features on clinical and pathological response, disease-free survival, and overall survival.
  
  
  RESULTS
  An objective clinical response to neoadjuvant chemotherapy was observed in 80% of patients, with 12% showing a complete pathological response. Among all clinical and pathological parameters, only the expression of hypoxia-inducible factor 1A was associated with a pathological response. A positive association was found between expression of aldehyde dehydrogenase and that of hypoxia-inducible factor 1A before and after chemotherapy. Aldehyde dehydrogenase expression was associated with expression of hypoxia inducible-factor 2A in tumors after neoadjuvant treatment. In a univariate analysis, prognosis was influenced by age, pathological response, metastasis to axillary lymph nodes after neoadjuvant chemotherapy, overexpression of hypoxia-inducible factor 2, and the presence of aldehyde dehydrogenase-positive cells within the primary tumor after neoadjuvant chemotherapy. In a multivariate analysis, only age and the presence of aldehyde dehydrogenase-positive cells after chemotherapy were associated with reduced overall survival.
  
  
  CONCLUSIONS
  The presence of aldehyde dehydrogenase-positive cells within the residual tumor after neoadjuvant chemotherapy is associated with an increase in the expression of hypoxia-inducible factor 2A and with poor prognosis in patients with locally advanced breast cancer.
authors.affiliation: Universidade de São Paulo, Hospital das Clínicas of the RibeirãoPreto School of Medicine, Breast Disease Division Department of Gynecology and Obstetrics, Ribeirão Preto/SP, Brazil. dtiezzi@usp.br
authors.forename: Daniel Guimarães
authors.initials: DG
authors.lastname: Tiezzi
authors.forename: Willian Simões
authors.initials: WS
authors.lastname: Clagnan
authors.forename: Larissa Raquel Mouro
authors.initials: LR
authors.lastname: Mandarano
authors.forename: Christiani Bisinoto
authors.initials: CB
authors.lastname: de Sousa
authors.forename: Heitor Ricardo Cosiski
authors.initials: HR
authors.lastname: Marana
authors.forename: Marcelo Guimarães
authors.initials: MG
authors.lastname: Tiezzi
authors.forename: Jurandyr Moreira
authors.initials: JM
authors.lastname: de Andrade
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007150:Immunohistochemistry; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000444:Aldehyde Dehydrogenase; D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D000099162:Endothelial PAS Domain-Containing Protein 1