Type 1 Nuclear Receptor Activity in Breast Cancer: Translating Preclinical Insights to the Clinic

Simple Summary: Breast cancer is the most common cancer affecting women, and the importance of NR function in breast cancer biology has been recognized since the turn of the 20(th) century. The nuclear receptor family of transcription factors is associated with cancer development and progression, informs diagnostic and prognostic outcomes, and is an established therapeutic target. Across all subtypes of breast cancer, crosstalk between NR pathways and other signalling pathways has also been demonstrated. Recent critical findings into modulating these NRs, particularly Type 1 NRs, have led to clinical trials and a greater understanding of their mechanism of action. Here, we reviewed the current preclinical insights into the role of Type 1 NRs in breast cancer that have served as a catalyst for clinical translation. The nuclear receptor (NR) family of transcription factors is intimately associated with the development, progression and treatment of breast cancer. They are used diagnostically and prognostically, and crosstalk between nuclear receptor pathways and growth factor signalling has been demonstrated in all major subtypes of breast cancer. The majority of breast cancers are driven by estrogen receptor alpha (ER), and anti-estrogenic therapies remain the backbone of treatment, leading to clinically impactful improvements in patient outcomes. This serves as a blueprint for the development of therapies targeting other nuclear receptors. More recently, pivotal findings into modulating the progesterone (PR) and androgen receptors (AR), with accompanying mechanistic insights into NR crosstalk and interactions with other proliferative pathways, have led to clinical trials in all of the major breast cancer subtypes. A growing body of evidence now supports targeting other Type 1 nuclear receptors such as the glucocorticoid receptor (GR), as well as Type 2 NRs such as the vitamin D receptor (VDR). Here, we reviewed the existing preclinical insights into nuclear receptor activity in breast cancer, with a focus on Type 1 NRs. We also discussed the potential to translate these findings into improving patient outcomes.