title: Low calpain-9 is associated with adverse disease-specific survival following endocrine therapy in breast cancer.
abstract: BACKGROUND
  The calpains are intracellular cysteine proteases that function in a variety of important cellular functions, including signalling, motility, apoptosis and survival. In breast cancer high calpain-1 and calpain-2 expression has been associated with adverse clinical outcome. Calpain-9 was thought to be exclusively expressed in the digestive tract; however recent studies have shown that this protein is also expressed in breast tissue.
  
  
  METHODS
  We investigated the expression of calpain-9 in a large cohort of early stage breast cancer patients (n = 783) using immunohistochemistry on a tissue microarray. Patients had long-term follow-up information available for analysis.
  
  
  RESULTS
  Low expression of calpain-9 was associated with patients over 40 years of age (P = 0.025), smaller tumour size (P = 0.001), lower tumour stage (P = 0.009), a more favourable Nottingham Prognostic Index value (P = 0.002) and positive oestrogen receptor status (P = 0.014). Calpain-9 expression was not associated with survival in the total patient cohort, however low calpain-9 expression was associated with adverse survival in patients who received endocrine therapy (P = 0.033), which remained significant in multivariate Cox regression analysis accounting for potential confounding factors (hazard ratio (HR) = 0.56, 95% confidence interval (95% CI) = 0.36-0.89, P = 0.013). Low calpain-9 expression was also associated with adverse survival in patients with an intermediate Nottingham Prognostic Index value (P = 0.009), and remained so in multivariate analysis (HR = 0.54, 95% CI = 0.36-0.82, P = 0.003).
  
  
  CONCLUSIONS
  This study suggests that calpain-9 may play a role in breast cancer and that low expression is associated with poorer patient clinical outcome following endocrine therapy. Validation studies are warranted as determining expression of calpain-9 may provide important prognostic information.
authors.forename: Jillian
authors.initials: J
authors.lastname: Davis
authors.forename: Stewart G
authors.initials: SG
authors.lastname: Martin
authors.forename: Poulam M
authors.initials: PM
authors.lastname: Patel
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Academic Clinical Oncology, University of Nottingham, Division of Cancer and Stem Cells, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham NG5 1 PB, UK. sarah.storr@nottingham.ac.uk.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Storr
mesh_terms: D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D002154:Calpain / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome; D047368:Tumor Burden; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C518121:CAPN9 protein, human; D002154:Calpain