Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer

J Natl Cancer Inst. 2003 Mar 5;95(5):353-61. doi: 10.1093/jnci/95.5.353.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetyltransferases
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Biomarkers, Tumor / metabolism*
  • Blotting, Western
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / surgery
  • Chemotherapy, Adjuvant
  • Drug Resistance, Neoplasm*
  • Estrogen Receptor Modulators / pharmacology*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histone Acetyltransferases
  • Humans
  • Nuclear Receptor Coactivator 3
  • Oncogene Proteins
  • Predictive Value of Tests
  • Prognosis
  • Receptor, ErbB-2 / metabolism*
  • Tamoxifen / pharmacology*
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured


  • Antineoplastic Agents, Hormonal
  • Biomarkers, Tumor
  • Estrogen Receptor Modulators
  • Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • Tamoxifen
  • Acetyltransferases
  • Histone Acetyltransferases
  • NCOA3 protein, human
  • Nuclear Receptor Coactivator 3
  • Receptor, ErbB-2