Trastuzumab treatment in human breast cancer is associated with over-expression of the retinoic acid receptor alpha (RARA).

Treatment with trastuzumab has been associated with an increased risk of central nervous system metastasis in patients with human breast cancer (1-5). We performed unbiased transcriptome profiling of primary tumors of patients treated with trastuzumab using published microarray and multiplexed gene expression datasets (6, 7) to understand the transcriptional makeup of breast tumors in the trastuzumab-treated patients. We found that the retinoid acid receptor alpha was among the genes most differentially expressed in the primary tumors of patients treated with trastuzumab; retinoid acid receptor alpha was expressed at significantly higher levels in tumors from patients with trastuzumab as compared to those not treated with trastuzumab. Increased retinoic acid receptor alpha expression is known to confer tamoxifen resistance to human breast cancers (8), and RARA expression is higher in tumors with higher proliferative capacity (9), suggesting that trastuzumab could contribute to resistance to endocrine therapy.