title: Hypoxic regulation and prognostic value of LAMP3 expression in breast cancer.
abstract: BACKGROUND
  LAMP3 is a newly described hypoxia regulated gene of potential interest in hypoxia-induced therapy resistance and metastasis. The prognostic value of LAMP3 in breast cancer was investigated.
  
  
  METHODS
  Expression levels of LAMP3 in breast cancer cell lines and patient tissues were determined by real-time polymerase chain reaction and in a tissue microarray by immunohistochemistry. Immunofluorescent staining was used to evaluate the distribution of LAMP3 in tumor xenografts relative to pimonidazole. Kaplan-Meier analysis as well as multivariate Cox regression survival analyses were performed.
  
  
  RESULTS
  LAMP3 was variably expressed in breast cancer cell lines and induced in an oxygen concentration-dependent manner. LAMP3 protein expression colocalized with hypoxic areas in breast cancer xenografts. LAMP3 mRNA was higher in breast tumors from patients with node-positive (P = .019) and/or steroid hormone receptor-negative tumors (P < .001). Breast cancer patients with high LAMP3 mRNA levels had more locoregional recurrences (P = .032 log-rank). This was limited to patients treated with lumpectomy and radiotherapy as primary treatment (n = 53, P = .009). No association with metastasis-free survival was found. In multivariate Cox regression analysis, LAMP3 remained as a statistically independent prognostic factor for locoregional recurrence (hazard ratio, 2.76; 95% confidence interval, 1.01-7.5; P = .048) after correction for menopausal status, histologic grade, tumor size, nodal status, therapy, and steroid hormone receptor status. LAMP3 protein in breast cancer tissue proved also to be of prognostic relevance.
  
  
  CONCLUSIONS
  Evidence was provided for an association of LAMP3 with tumor cell hypoxia in breast cancer xenografts. In the current breast cancer cohorts, LAMP3 had independent prognostic value.
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. A.Nagelkerke@rther.umcn.nl
authors.forename: Anika
authors.initials: A
authors.lastname: Nagelkerke
authors.forename: Hilda
authors.initials: H
authors.lastname: Mujcic
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.forename: Bradly G
authors.initials: BG
authors.lastname: Wouters
authors.forename: Hanneke W M
authors.initials: HW
authors.lastname: van Laarhoven
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D051907:Lysosomal Membrane Proteins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics*; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D010100:Oxygen / Q000378:metabolism*; D011379:Prognosis; D059666:Lysosomal-Associated Membrane Protein 3
chemical_list: D051907:Lysosomal Membrane Proteins; D009363:Neoplasm Proteins; D010100:Oxygen; C114233:LAMP3 protein, human; D059666:Lysosomal-Associated Membrane Protein 3