title: ALDH(+)/CD44(+) cells in breast cancer are associated with worse prognosis and poor clinical outcome.
abstract: BACKGROUND
  Breast cancer stem cells (BCSCs) play essential roles in tumor metastasis and contribute to remarkably negative clinical outcomes. Recently, aldehyde dehydrogenase (ALDH) and CD44 positivity (ALDH(+)/CD44(+)) was identified as a marker of BCSCs in vitro/in vivo studies. The aim of this study was to evaluate the prevalence of ALDH(+)/CD44(+) cells in breast cancer and the association of these two markers with clinicopathological features and clinical outcomes.
  
  
  METHODS
  We investigated the prevalence of ALDH1A3(+)/CD44(+) cells in a cohort of 144 formalin-fixed, paraffin-embedded (FFPE) breast cancer tissues. The tissues were stained for ALDH1A3 and CD44 by single and dual immunohistochemistry (dIHC). The associations among the prevalence of ALDH1A3(+)/CD44(+) cells, the clinicopathological features and the clinical outcomes of the patients were also analyzed.
  
  
  RESULTS
  ALDH1A3(+)/CD44(+) cells were present in 39 patients (27.1%). By the Mann-Whitney U test, the Pearson Chi-square test or Fisher's exact test, it was demonstrated that the prevalence of ALDH1A3(+)/CD44(+) cells was closely correlated with larger tumor size (p=0.001), nodal metastasis status (p=0.043), more advanced clinical stage (p=0.021) and distant metastasis after initial surgery (p=0.001). In a univariate survival analysis, the presence of ALDH1A3(+)/CD44(+) tumor cells had a significant negative association with both disease-free survival (DFS) and overall survival (OS) (pDFS<0.001; pOS<0.001). The negative clinical outcomes in ALDH1A3(+)/CD44(+) tumors were further confirmed by a multivariate analysis using Cox proportional hazard models (pDFS<0.001, HR=3.155; pOS=0.001, HR=3.193). This was also true with respect to the clinical treatment regimens of chemotherapy (pDFS<0.001; pOS=0.001), radiotherapy (pDFS=0.004; pOS=0.004), and endocrine therapy (pDFS<0.001; pOS<0.001).
  
  
  CONCLUSIONS
  In summary, our results indicate that the prevalence of ALDH1A3(+)/CD44(+) tumor cells in breast cancer is significantly associated with worse prognostic factors and favors a poor prognosis.
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Tianjie
authors.initials: T
authors.lastname: Pu
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wei
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Hongying
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Cancer Center and Laboratory of Molecular Diagnosis of Cancer, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Cancer Center and Laboratory of Molecular Diagnosis of Cancer, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Chen
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Bu
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: fengye@scu.edu.cn.
authors.forename: Feng
authors.initials: F
authors.lastname: Ye
mesh_terms: D000328:Adult; D000368:Aged; D000445:Aldehyde Oxidoreductases / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D018960:Hyaluronan Receptors; D000445:Aldehyde Oxidoreductases; C018699:aldehyde dehydrogenase (NAD(P)+)
keywords: ALDH(+)/CD44(+) cells; Breast cancer stem cell; Breast neoplasm; Metastasis; Poor prognosis