title: TSC22D1 and PSAP predict clinical outcome of tamoxifen treatment in patients with recurrent breast cancer.
abstract: Purpose Two genes, TSC22 domain family, member 1 (TSC22D1) and prosaposin (PSAP) were identified in an in vitro functional screen for genes having a causative role in tamoxifen resistance. These genes were also present in our previously established 81-gene signature for resistance to first-line tamoxifen therapy. The aim of this study was to investigate the predictive value of these genes for tamoxifen therapy failure in patients with recurrent breast cancer. Experimental Design The mRNA levels of TSC22D1 and PSAP were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in 223 estrogen receptor-positive primary breast tumors of patients with recurrent disease treated with first-line tamoxifen therapy. The main objective of this study was the length of progression-free survival (PFS). Results High mRNA levels of TSC22D1 and PSAP were significantly associated with shorter PFS and both were independent of the traditional predictive factors (HR = 1.30, 95% CI = 1.04-1.64 P = 0.023; and HR = 1.40, 95% CI = 1.03-1.88, P = 0.029, respectively). In multivariate analysis, patients with high mRNA levels of both genes associated significantly with no clinical benefit (OR = 0.19, 95% CI = 0.06-0.62, P = 0.006) and had the shortest PFS (HR = 2.05, 95% CI = 1.29-3.25, P = 0.002). Conclusion These results confirm our previous in vitro and tumor-related findings and are indicative for the failure of tamoxifen treatment in breast-cancer patients. Both TSC22D1 and PSAP are associated with clinical outcome and may have a functional role in therapy resistance.
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Room Be 432, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: Meijer
authors.forename: Maurice P H M
authors.initials: MP
authors.lastname: Jansen
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.forename: Kirsten
authors.initials: K
authors.lastname: Ruigrok-Ritstier
authors.forename: Iris L
authors.initials: IL
authors.lastname: van Staveren
authors.forename: Anieta M
authors.initials: AM
authors.lastname: Sieuwerts
authors.forename: Ton
authors.initials: T
authors.lastname: van Agthoven
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Lambert C J
authors.initials: LC
authors.lastname: Dorssers
authors.forename: Els M J J
authors.initials: EM
authors.lastname: Berns
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis*; D012334:RNA, Neoplasm / Q000032:analysis*; D018714:Radiotherapy, Adjuvant; D012097:Repressor Proteins / Q000235:genetics*; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049231:Saposins / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020847:Estrogen Receptor Modulators; C483345:PSAP protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D049231:Saposins; C099726:TSC22D1 protein, human; D013629:Tamoxifen