Lipid-sensors, enigmatic-orphan and orphan nuclear receptors as therapeutic targets in breast-cancer

Abstract

Breast-cancer is heterogeneous and consists of various groups with different biological characteristics. Innovative pharmacological approaches accounting for this heterogeneity are needed. The forty eight human Nuclear-Hormone-Receptors are ligand-dependent transcription-factors and are classified into Endocrine-Receptors, Adopted-Orphan-Receptors (Lipid-sensors and Enigmatic-Orphans) and Orphan-receptors. Nuclear-Receptors represent ideal targets for the design/synthesis of pharmacological ligands. We provide an overview of the literature available on the expression and potential role played by Lipid-sensors, Enigmatic-Orphans and Orphan-Receptors in breast-cancer. The data are complemented by an analysis of the expression levels of each selected Nuclear-Receptor in the PAM50 breast-cancer groups, following re-elaboration of the data publicly available. The major aim is to support the idea that some of the Nuclear-Receptors represent largely unexploited therapeutic-targets in breast-cancer treatment/chemo-prevention. On the basis of our analysis, we conclude that the Lipid-Sensors, NR1C3, NR1H2 and NR1H3 are likely to be onco-suppressors in breast-cancer. The Enigmatic-Orphans, NR1F1 NR2A1 and NR3B3 as well as the Orphan-Receptors, NR0B1, NR0B2, NR1D1, NR2F1, NR2F2 and NR4A3 exert a similar action. These Nuclear-Receptors represent candidates for the development of therapeutic strategies aimed at increasing their expression or activating them in tumor cells. The group of Nuclear-Receptors endowed with potential oncogenic properties consists of the Lipid-Sensors, NR1C2 and NR1I2, the Enigmatic-Orphans, NR1F3, NR3B1 and NR5A2, as well as the Orphan-Receptors, NR2E1, NR2E3 and NR6A1. These oncogenic Nuclear-Receptors should be targeted with selective antagonists, reverse-agonists or agents/strategies capable of reducing their expression in breast-cancer cells.

The orphan nuclear receptor estrogen-related receptor beta (ERRβ) in triple-negative breast cancer

“…2b). In TCGA data, we confirmed the previously published findings of Garattini, et al [13] and found that BLBC patients had significantly lower ESRRB expression compared to luminal A patients ( Fig. 2c).…”

“…Our 2016 publication showed that BLBC patients with high ESRRB mRNA expression have significantly improved distant-metastases free, and recurrence-free survival in comparison to patients with low expression [11]. Previous publications have shown that BLBC patients overall have significantly lower ESRRB mRNA expression in comparison to other breast cancer subtypes [12,13].…”

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

“…No probesets that can detect ERRβsf (alone or in combination with others) are available on this Affymetrix platform. Garattini et al's recent analysis of nuclear receptor superfamily expression in The Cancer Genome Atlas (TCGA) breast cancer RNAseq data shows that total ESRRB expression (referred to in the manuscript as NR3B2) is significantly reduced in breast tumors vs. normal breast tissue, with lowest expression in the Luminal B and Basal-Like molecular subtypes [90]. While preliminary, these data suggest that ERRβ2 may be a good prognostic factor in TNBC, and are consistent with the findings we present here that implicate the activated ERRβ2 splice variant as a potent inhibitor of mitotic progression in breast cancer cells, including triple negative models.…”

Loss of NR2E3 represses AHR by LSD1 reprogramming, is associated with poor prognosis in liver cancer

“…We further revealed that environmentally induced oxidative stress decreased the level and homo-dimerization activity of NR2E3, resulting in a repressive epigenetic status of ESR1 gene promoter by LSD1 recruitment, consequently turning off ESR1 expression, indicating that NR2E3 is an oxidative stress-responsive epigenetic regulator 7 . Furthermore, ligand-activated potential of NR2E3 like other orphan nuclear receptors will provide opportunity to develop therapeutic targets in the future, although no ligand identified yet 8 , 9 .…”