title: Immunohistochemical determination of the miR-1290 target arylamine N-acetyltransferase 1 (NAT1) as a prognostic biomarker in breast cancer.
abstract: BACKGROUND
  There are many molecular differences between estrogen receptor α (ERα)-positive and ER-negative breast cancers. Recent analyses have shown that the former can be divided into two subtypes, luminal A and luminal B. These differ in response to endocrine therapy and chemotherapy, and in prognosis. In a previous study, we found that microRNA (miR)-1290 that was significantly down-regulated in luminal A tumors and its potential target arylamine N-acetyltransferase 1 (NAT1). The aim of the present study was to determine whether NAT1 is a bona fide target of miR-1290, and to investigate the impact of NAT1 on breast cancer prognosis.
  
  
  METHODS
  Luciferase reporter assays were employed to validate NAT1 as a putative miR-1290 target gene. Expression of NAT1, ERα, progesterone receptor (PgR) and HER2 was analyzed in 394 breast cancer samples by immunohistochemistry.
  
  
  RESULTS
  NAT1 was confirmed to be a direct target of miR-1290. Levels of expression of NAT1 were positively correlated with those of ERα (P < 0.0001) and PgR (P < 0.0001), but negatively correlated with both tumor grade and size (P < 0.0001). Kaplan-Meier analysis showed that the presence of NAT1 was significantly associated with increased overall survival (OS) (P = 0.0416) in these patients. Similarly, significant associations of NAT1 with disease-free survival (DFS) (P = 0.0048) and OS (P = 0.0055) in those patients who received adjuvant endocrine therapy with tamoxifen (n = 176) were found. Moreover, NAT1 was also significantly associated with increased DFS (P = 0.0025) and OS (P = 0.0007) in the subset of lymph node-positive patients (n = 147). Univariate and multivariate analyses showed significant associations between levels of NAT1 and DFS (P = 0.0005 and 0.019, respectively).
  
  
  CONCLUSIONS
  We report that miR-1290 directly targets the NAT1 3'-UTR and that NAT1 protein expression is correlated with improved OS of breast cancer patients. NAT1 is a possible prognostic biomarker for lymph node-positive breast cancer. Thus, miR-1290 and its target NAT1 are associated with important characteristics of breast cancer.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Endo
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yamashita
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Shinya
authors.initials: S
authors.lastname: Sato
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Yoshimoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Asano
authors.forename: Yukari
authors.initials: Y
authors.lastname: Hato
authors.forename: Yu
authors.initials: Y
authors.lastname: Dong
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. t.toyama@med.nagoya-cu.ac.jp.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Toyama
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D011379:Prognosis; D034622:RNA Interference; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics*; D047368:Tumor Burden
chemical_list: D020413:3' Untranslated Regions; D015415:Biomarkers; D007527:Isoenzymes; C574604:MIRN1290 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1