Stromal expression of beta-arrestin-1 predicts clinical outcome and tamoxifen response in breast cancer.

摘要

The G-protein coupled receptor associated protein beta-arrestin-1 is crucial for the regulation of numerous biological processes involved in cancer progression, such as intracellular signaling and cell motility. The encoding gene ARRB1 is harbored in the same chromosomal region as the CCND1 gene (11q13). Amplification of CCND1, frequently encountered in breast cancer, often involves coamplification of additional oncogenes, as well as deletion of distal 11q genes. We investigated the clinical relevance of beta-arrestin-1 in breast cancer and elucidated a potential link between beta-arrestin-1 expression and CCND1 amplification. beta-Arrestin-1 protein expression was evaluated in two breast cancer patient cohorts, comprising 179 patients (cohort I) and 500 patients randomized to either tamoxifen or no adjuvant treatment (cohort II). Additionally, migration after beta-arrestin-1 overexpression or silencing was monitored in two breast cancer cell lines. Overexpression of beta-arrestin-1 reduced the migratory propensity of both cell lines, whereas silencing increased migration. In cohort I, high expression of stromal beta-arrestin-1 was linked to reduced patient survival, whereas in cohort II both high and absent stromal expression predicted a poor clinical outcome. Patients exhibiting low or moderate levels of stromal beta-arrestin-1 did not benefit from tamoxifen, in contrast to patients exhibiting absent or high expression. Furthermore, CCND1 amplification was inversely correlated with tumor cell expression of beta-arrestin-1, indicating ARRB1 gene deletion in CCND1-amplified breast cancers.