Amplified in Breast Cancer 1 in Human Epidermal Growth Factor Receptor–Positive Tumors of Tamoxifen-Treated Breast Cancer Patients

Abstract

Purpose: Amplified in breast cancer 1 (AIB1) is a member of the p160/steroid receptor coactivators family and is involved in estrogen-dependent gene transcription by reducing the antagonistic activity of tamoxifen-bound estrogen receptor-a (ER-a).The present study was carried out to test the hypothesis that AIB1protein expression and/or gene amplification mediates tamoxifen resistance in breast cancer. Experimental Design: Immunohistochemistry using AIB1 antibody and fluorescence in situ hybridization using probes specific forAIB1and chromosome 20 was done on 402 ER-a^positive tamoxifen-treated breast cancers. Results: AIB1overexpression was not associated with relapse during treatment with tamoxifen. In contrast, high AIB1expression in patients with human epidermal growth factor receptor (HER) 2^and HER3-overexpressing tumors or tumors expressing one or more of HER1, HER2, or HER3 (HER1-3 positive) was associated with an increased risk of relapse on tamoxifen [hazard ratio, 2.20; 95% confidence interval, 1.07-3.52 (P = 0.0416); hazard ratio, 2.42; 95% confidence interval, 1.32-4.43 (P = 0.0030), respectively]. AIB1 gene amplification was observed in 18 of 362 (5%) patients. High AIB1 gene copy number had no effect on overall or disease-free survival. Conclusions: Data presented here support a role forAIB1expression on relapse during tamoxifen treatment in hormone-responsive HER-expressing clinical breast cancers and support clinical evidence, suggesting a cross-talk between ER-a and growth factor receptor pathways through changes in expression of specific coactivator proteins, such as AIB1. This study highlights the potential that tumor profiling, using multiple markers of treatment response, may improve patient selection for endocrine treatment, such as tamoxifen or aromatase inhibitors.

Epidermal growth factor receptor (EGFR) and the estrogen receptor modulator amplified in breast cancer (AIB1) for predicting clinical outcome after adjuvant tamoxifen in breast cancer

“…Also an in vitro experiment has demonstrated that AIB1 expression is increased in anti-estrogen resistant cells [18]. The recently presented data from Kirkegaard and co-workers using immunohistochemistry based evaluation of AIB1 demonstrated that the AIB1 subgroup did not have an increased risk of relapse during tamoxifen treatment in hormone receptor positive disease, although the combination of HER1-3 and AIB1 defined a subset of patients with an increased risk of relapse during tamoxifen treatment in the ER positive cohort [11]. However, the fraction of patients defined as AIB1 high was not presented and furthermore chemo-endocrine treatment was given to 25% of the included patients which make direct comparisons with our study difficult.…”

“…(Amplified In Breast cancer-1) is a co-activator of ER and the estrogen agonist activity of tamoxifen can be enhanced by high levels of AIB1 [10,11]. However, quite opposite results have been obtained in another study, showing that patients with high AIB1 nuclear expression tended to be successfully treated by hormonal therapy [12].…”

Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth

“…High-level of AIB1 expression has been associated with a poor prognosis and non-responsiveness to tamoxifen in ERα-positive breast cancers, with AIB1-positive patients also over-expressing HER1, 2 or 3, being most likely to relapse on tamoxifen [10,34,35]. These findings indicate that crosstalk between ERα, AIB1 and growth factor receptor pathways are important in determining response and resistance to tamoxifen.…”

Estrogen Receptor and Progesterone Receptor As Predictive Biomarkers of Response to Endocrine Therapy: A Prospectively Powered Pathology Study in the Tamoxifen and Exemestane Adjuvant Multinational Trial

“…1 However, a significant group with hormone receptor-positive (HRec-positive) tumors exhibited resistance, either acquired or de novo, to tamoxifen therapy. 2,3 Several resistance mechanisms are hypothesized, including signaling via human epidermal growth factor receptor (EGFR) homolog 2 (HER2), EGFR/ HER1, and HER3 [4][5][6][7] signaling pathways, 8,9 or loss of ER-mediated gene regulation. 10,11 Differential sensitivity to endocrine agents (eg, aromatase inhibitors [AIs] v tamoxifen) has been linked to bypassing resistance pathways.…”