title: Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer.
abstract: BACKGROUND
  AIB1 (SRC-3) is an estrogen receptor (ER) coactivator that, when overexpressed in cultured cells, can reduce the antagonist activity of tamoxifen-bound ERs. Signaling through the HER-2 receptor pathway activates AIB1 by phosphorylation. To determine whether high AIB1 expression alone or together with HER-2 reduces the effectiveness of tamoxifen in breast cancer patients, we quantified expression of AIB1 and HER-2 in tumors from breast cancer patients with long-term clinical follow-up who received either no adjuvant therapy or adjuvant tamoxifen therapy after breast cancer surgery.
  
  
  METHODS
  AIB1 and HER-2 protein levels in tumors from 316 breast cancer patients were determined using western blot analysis. Molecular variables (e.g., expression of AIB1, ER, progesterone receptor, p53, Bcl-2), tumor characteristics, and patient outcome were assessed using Spearman rank correlation. Disease-free survival (DFS) curves were derived from Kaplan-Meier estimates, and the curves were compared by log-rank tests. The effect of AIB1 on DFS adjusted for other prognostic factors was assessed by multivariable analysis using the Cox proportional hazards model. All statistical tests were two-sided.
  
  
  RESULTS
  High AIB1 expression in patients not receiving adjuvant tamoxifen therapy was associated with better prognosis and longer DFS (P =.018, log-rank test). In contrast, for patients who did receive tamoxifen therapy, high AIB1 expression was associated with worse DFS (P =.049, log-rank test), which is indicative of tamoxifen resistance. The test for interaction between AIB1 expression and tamoxifen therapy was statistically significant (P =.004). When expression of AIB1 and HER-2 were considered together, patients whose tumors expressed high levels of both AIB1 and HER-2 had worse outcomes with tamoxifen therapy than all other patients combined (P =.002, log-rank test).
  
  
  CONCLUSIONS
  The antitumor activity of tamoxifen in patients with breast cancer may be determined, in part, by tumor levels of AIB1 and HER-2. Thus, AIB1 may be an important diagnostic and therapeutic target.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. kosborne@breastcenter.tmc.edu
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Valerie
authors.initials: V
authors.lastname: Bardou
authors.forename: Torsten A
authors.initials: TA
authors.lastname: Hopp
authors.forename: Gary C
authors.initials: GC
authors.lastname: Chamness
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.forename: Suzanne A W
authors.initials: SA
authors.lastname: Fuqua
authors.forename: Jiemin
authors.initials: J
authors.lastname: Wong
authors.forename: D Craig
authors.initials: DC
authors.lastname: Allred
authors.forename: Gary M
authors.initials: GM
authors.lastname: Clark
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
mesh_terms: D000123:Acetyltransferases; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051548:Histone Acetyltransferases; D006801:Humans; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000123:Acetyltransferases; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D020847:Estrogen Receptor Modulators; D051548:Histone Acetyltransferases; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; D015534:Trans-Activators; D014157:Transcription Factors; C538866:NCOA3 protein, human