Orphan nuclear receptors in breast cancer pathogenesis and therapeutic response

Abstract

Nuclear receptors comprise a large family of highly conserved transcription factors that regulate many key processes in normal and neoplastic tissues. Most nuclear receptors share a common, highly conserved domain structure that includes a carboxy-terminal ligand-binding domain. However, a subgroup of this gene family is known as the orphan nuclear receptors because to date there are no known natural ligands that regulate their activity. Many of the 25 nuclear receptors classified as orphan play critical roles in embryonic development, metabolism, and the regulation of circadian rhythm. Here, we review the emerging role(s) of orphan nuclear receptors in breast cancer, with a particular focus on two of the estrogen-related receptors (ERRalpha and ERRgamma) and several others implicated in clinical outcome and response or resistance to cytotoxic or endocrine therapies, including the chicken ovalbumin upstream promoter transcription factors, nerve growth factor-induced B, DAX-1, liver receptor homolog-1, and retinoic acid-related orphan receptor alpha. We also propose that a clearer understanding of the function of orphan nuclear receptors in mammary gland development and normal mammary tissues could significantly improve our ability to diagnose, treat, and prevent breast cancer.

Fig. 1. Nuclear receptor domain structure

AF1, activation function-1; DBD, DNA-binding domain; CTE, carboxy-terminal extension; NLS, nuclear localization sequence; LBD, ligand-binding domain; AF2, activation function-2.

Fig. 2. Elevated ERRγ expression in Tamoxifen-resistant breast tumors

Re-analysis of gene expression microarray data from Ma et al. shows that pre-treatment ERRγ expression is significantly increased in the tumors of breast cancer patients who recurred within 5 years of Tamoxifen therapy (p=0.017, Mann-Whitney rank sum test).