title: PSMD9 expression predicts radiotherapy response in breast cancer.
abstract: BACKGROUND
  More than 50% of cancer patients are recommended to receive radiotherapy. Recommendations are based mainly on clinical and pathological factors and not intrinsic tumour radio-sensitivity. Use of radiotherapy according to predictive markers would potentially reduce costly over-treatment, and improve the treatment risk-benefit ratio and cancer outcomes. Tumour expression of the 26S proteasome has been reported to predict radiotherapy response: low expression was associated with higher rates of local recurrence after radiotherapy, suggesting that low proteasome expression and activity was associated with radio-resistance. However, this conclusion is at odds with the emerging use of proteasome inhibitors as radio-sensitizers. Our aim was to further analyse the relevance of 26S proteasome expression, focussing specifically on the PSMD9 subunit, in the largest clinical cohort to date, and to investigate the functional role of PSMD9 in radio-sensitivity in breast cancer cell lines.
  
  
  METHODS
  We examined expression of PSMD9 using immunohistochemistry in a cohort of 157 breast cancer patients, including 32 cases (20.4%) that subsequently developed local recurrences. The value of expression as a prognostic or radiotherapy predictive marker was tested using Kaplan-Meier and Cox regression analyses. PSMD9 function was examined in breast cancer cell lines MCF7 and MDA-MB-231 using siRNA knock-downs and colony forming assays after irradiation.
  
  
  RESULTS
  Low tumour PSMD9 expression was significantly associated with a reduced incidence of local recurrence in patients receiving adjuvant radiotherapy (univariate log rank p = 0.02; multivariate regression p = 0.009), but not in those treated without radiotherapy, suggesting that low PSMD9 expression was associated with relative tumour radio-sensitivity. In support of this, reduction of PSMD9 expression using siRNA in breast cancer cell lines in vitro sensitized cells to radiotherapy.
  
  
  CONCLUSIONS
  We conclude that PSMD9 expression may predict radiotherapy benefit, with low expression indicative of relative radio-sensitivity, the opposite of previous reports relating to 26S proteasome expression. Our conclusion is compatible with use of proteasome inhibitors as radio-sensitizers, and highlights PSMD9 as a potential target for radio-sensitizing drugs.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Langlands
authors.forename: David
authors.initials: D
authors.lastname: Dodwell
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hanby
authors.forename: Kieran
authors.initials: K
authors.lastname: Horgan
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Millican-Slater
authors.forename: Valerie
authors.initials: V
authors.lastname: Speirs
authors.forename: Eldo T
authors.initials: ET
authors.lastname: Verghese
authors.affiliation: Leeds Institutes of Molecular Medicine, University of Leeds, Leeds, UK. medlsmi@leeds.ac.uk.
authors.forename: Laura
authors.initials: L
authors.lastname: Smith
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hughes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D018714:Radiotherapy, Adjuvant; D012044:Regression Analysis; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: C114476:PSMD9 protein, human; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D046988:Proteasome Endopeptidase Complex