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

Abstract

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 α (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.

βArrestin1 regulates glucocorticoid receptor mitogenic signaling in castration‐resistant prostate cancer

“…Notably, recent results link high primary tumor GR expression (and associated increased glucocorticoid-mediated gene expression) to rapid estrogen-independent breast cancer progression, 38 although the possible role of βArr1 remains to be demonstrated.…”

“…Inhibition of the βArr1‐GR signaling axis may be beneficial in the treatment of patients diagnosed with GR‐mediated CRPC disease. Notably, recent results link high primary tumor GR expression (and associated increased glucocorticoid‐mediated gene expression) to rapid estrogen‐independent breast cancer progression, 38 although the possible role of βArr1 remains to be demonstrated.…”

Estrogen Receptor Bio-Activities Determine Clinical Endocrine Treatment Options in Estrogen Receptor-Positive Breast Cancer

“… 6 , 7 PR is often measured along with ER, due to the initial observation that PR is induced by estrogen 100 and competitively binds and alters the chromatin binding sites of ER, 101 changing the transcriptional target genes associated with proliferation into that with cell cycle arrest, apoptosis, and differentiation. 102 , 103 Clinical studies also found that patients with ER+, PR+ BC are more likely to respond to ET than patients with ER+, PR−. 104 However, it is not clear that PR has an independent predictive value for adjuvant ET, so the detection of PR exists only as a supplementary reference for ER.…”

Mechanisms behind context-dependent role of glucocorticoids in breast cancer progression

“…2h ). Extensive crosstalk between GR signaling and other steroid receptors, including ER, PR, androgen receptor (AR), and mineralocorticoid receptor (MR), have been described in breast cancer in detail [ 39 , 64 , 105 - 107 ].…”

“…ER crosstalk with both PR and AR are the best-characterized models of nuclear receptor interactions in breast cancer, but lately, the interaction of ER with GR has been emerged [ 105 - 107 ].…”