Observational studies of human endometrium and endometrial cancer : the role of steroids and steroid hormone receptors in tissue proliferation, differentiation and malignant transformation

Preclinical and/or clinical evidence has indicated a potential role of steroid hormone-mediated signaling pathways in the development of various neoplastic diseases, while precise mechanisms for the functions of specific receptors remain poorly understood. Specifically, in urothelial cancer where sex-related differences particularly in its incidence are noted, activation of sex hormone receptors, such as androgen receptor and estrogen receptor-β, has been associated with the induction of tumor development. More recently, glucocorticoid receptor has been implied to function as a suppressor of urothelial tumorigenesis. This article summarizes and discusses available data suggesting that steroid hormone receptors, including androgen receptor, estrogen receptor-α, estrogen receptor-β, glucocorticoid receptor, progesterone receptor and vitamin D receptor, as well as their related signals, contribute to modulating urothelial tumorigenesis.

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A conserved mechanism of sirtuin signalling through steroid hormone receptors

Bioscience Reports ◽

10.1042/bsr20193535 ◽

2019 ◽

Vol 39 (12) ◽

Cited By ~ 3

Author(s):

Henry K. Bayele

Keyword(s):

Drug Targets ◽

Metabolic Regulation ◽

Hormone Receptors ◽

Steroid Receptors ◽

Steroid Hormone ◽

Steroid Hormone Receptors ◽

Nuclear Receptor Coregulators ◽

Dafachronic Acid ◽

Important Drug

Abstract SIRT1 and orthologous sirtuins regulate a universal mechanism of ageing and thus determine lifespan across taxa; however, the precise mechanism remains vexingly polemical. They also protect against many metabolic and ageing-related diseases by dynamically integrating several processes including autophagy, proteostasis, calorie restriction, circadian rhythmicity and metabolism. These sirtuins are therefore important drug targets particularly because they also transduce allosteric signals from sirtuin-activating compounds such as resveratrol into increased healthspan in evolutionarily diverse organisms. While many of these functions are apparently regulated by deacetylation, that mechanism may not be all-encompassing. Since gonadal signals have been shown to regulate ageing/lifespan in worms and flies, the present study hypothesized that these sirtuins may act as intermediary factors for steroid hormone signal transduction. Accordingly, SIRT1 and its orthologues, Sir2 and Sir-2.1, are shown to be veritable nuclear receptor coregulators that classically coactivate the oestrogen receptor in the absence of ligand; coactivation was further increased by 17β-oestradiol. Remarkably in response to the worm steroid hormone dafachronic acid, SIRT1 reciprocally coactivates DAF-12, the steroid receptor that regulates nematode lifespan. These results suggest that steroid hormones may co-opt and modulate a phyletically conserved mechanism of sirtuin signalling through steroid receptors. Hence, it is interesting to speculate that certain sirtuin functions including prolongevity and metabolic regulation may be mechanistically linked to this endocrine signalling pathway; this may also have implications for understanding the determinative role of gonadal steroids such as oestradiol in human ageing. At its simplest, this report shows evidence for a hitherto unknown deacetylation-independent mechanism of sirtuin signalling.

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Clinical and genomic crosstalk between glucocorticoid receptor and estrogen receptor α in endometrial cancer

10.1101/199448 ◽

2017 ◽

Cited By ~ 1

Author(s):

Jeffery M. Vahrenkamp ◽

Chieh-Hsiang Yang ◽

Adriana C. Rodriguez ◽

Aliyah Almomen ◽

Kristofer C. Berrett ◽

...

Keyword(s):

Estrogen Receptor ◽

Endometrial Cancer ◽

Glucocorticoid Receptor ◽

Hormone Receptors ◽

Steroid Hormone ◽

Estrogen Receptor Α ◽

Steroid Hormone Receptors ◽

Uterine Growth ◽

Opposing Effects

SummarySteroid hormone receptors are simultaneously active in many tissues and are capable of altering each other’s function. Estrogen receptor α (ER) and glucocorticoid receptor (GR) are expressed in the uterus and their ligands have opposing effects on uterine growth. In endometrial tumors with high ER expression, we surprisingly found that expression of GR is associated with poor prognosis. Dexamethasone reduced normal uterine growth in vivo; however, this growth inhibition was abolished in estrogen-induced endometrial hyperplasia. We observed low genomic binding site overlap when ER and GR are induced with their respective ligands; however, upon simultaneous induction they co-occupy more sites. GR binding is significantly altered by estradiol with GR recruited to ER bound loci that become more accessible upon estradiol induction. Gene expression responses to co-treatment were more similar to estradiol, but with novel regulated genes. Our results suggest phenotypic and molecular interplay between ER and GR in endometrial cancer.

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