Regulation of mineralocorticoid receptor activation by circadian protein TIMELESS.

The mineralocorticoid receptor (MR) is a ligand-activated transcription factor that regulates cardiorenal physiology and disease. Ligand-dependent MR transactivation involves a conformational change in the MR and recruitment of coregulatory proteins to form a unique DNA-binding complex at the hormone response element in target gene promoters. Differences in the recruitment of coregulatory proteins can promote tissue-, ligand- or gene-specific transcriptional outputs.

Mineralocorticoid receptor actions in cardiovascular development and disease.

Mineralocorticoid receptors (MRs) are transcriptional regulators that mediate the diverse physiological and pathophysiological actions of corticosteroid hormones across many tissues. In the kidney aldosterone control of sodium/water resorption via DNA-binding actions of the MR is established. MRs also regulate tissues not involved in electrolyte homeostasis such as the heart, adipose tissue, brain, and inflammatory cells where the MRs can respond to both aldosterone and cortisol.

A tumour suppressive relationship between mineralocorticoid and retinoic acid receptors activates a transcriptional program consistent with a reverse Warburg effect in breast cancer.

Background: The role of nuclear receptors in both the aetiology and treatment of breast cancer is exemplified by the use of the oestrogen receptor (ER) as a prognostic marker and treatment target. Treatments targeting the oestrogen signalling pathway are initially highly effective for most patients. However, for the breast cancers that fail to respond, or become resistant, to current endocrine treatments, the long-term outlook is poor.

Endocrine aspects of ACE2 regulation: RAAS, steroid hormones and SARS-CoV-2.

Coronavirus disease (COVID-19) is caused by a new strain of coronavirus, the severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2. At the time of writing, SARS-CoV-2 has infected over 5 million people worldwide. A key step in understanding the pathobiology of the SARS-CoV-2 was the identification of -converting enzyme 2 (ACE2) as the receptor for SARS-CoV-2 to gain entry into host cells.

Cardiomyocyte transcription is controlled by combined MR and circadian clock signalling.

We previously identified a critical pathogenic role for MR activation in cardiomyocytes that included a potential interaction between the MR and the molecular circadian clock. While glucocorticoid regulation of the circadian clock is undisputed, MR interactions with circadian clock signalling are limited. We hypothesised that the MR influences cardiac circadian clock signalling, and vice versa.

Timeless Is a Novel Estrogen Receptor Co-activator Involved in Multiple Signaling Pathways in MCF-7 Cells.

Activation of estrogen receptor α (ERα) stimulates cell division and tumor growth by modulating the expression of ERα target genes. This activation involves the recruitment of specific proteins with activities that are still not fully understood. Timeless, the human homolog of the Drosophila gene involved in circadian rhythm, was previously shown to be a strong predictor of tamoxifen relapse, and is involved in genomic stability and cell cycle control.

Deoxycorticosterone/Salt-Mediated Cardiac Inflammation and Fibrosis Are Dependent on Functional CLOCK Signaling in Male Mice.

Activation of the mineralocorticoid receptor (MR) promotes inflammation, fibrosis, and hypertension. Clinical and experimental studies show that MR antagonists have significant therapeutic benefit for all-cause heart failure; however, blockade of renal MRs limits their widespread use. Identification of key downstream signaling mechanisms for the MR in the cardiovascular system may enable development of targeted MR antagonists with selectivity for pathological MR signaling and lower impact on physiological renal electrolyte handling.

The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma.

Drugs that target the Renin-Angiotensin System (RAS) have recently come into focus for their potential utility as cancer treatments. The use of Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme (ACE) Inhibitors (ACEIs) to manage hypertension in cancer patients is correlated with improved survival outcomes for renal, prostate, breast and small cell lung cancer. Previous studies demonstrate that the Angiotensin Receptor Type I (AT1R) is linked to breast cancer pathogenesis, with unbiased analysis of gene-expression studies identifying significant up-regulation of AGTR1, the gene encoding AT1R in ER+ve/HER2-ve tumors correlating with poor prognosis.

Insights into Orphan Nuclear Receptors as Prognostic Markers and Novel Therapeutic Targets for Breast Cancer.

There is emerging evidence asserting the importance of orphan nuclear receptors (ONRs) in cancer initiation and progression. In breast cancer, there is a lot unknown about ONRs in terms of their expression profile and their transcriptional targets in the various stages of tumor progression. With the classification of breast tumors into distinct molecular subtypes, we assess ONR expression in the different breast cancer subtypes and with patient outcomes.

GEMIN4 functions as a coregulator of the mineralocorticoid receptor.

The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily. Pathological activation of the MR causes cardiac fibrosis and heart failure, but clinical use of MR antagonists is limited by the renal side effect of hyperkalemia. Coregulator proteins are known to be critical for nuclear receptor-mediated gene expression.

Estradiol regulates Tumor Necrosis Factor-α expression and secretion in Estrogen Receptor positive breast cancer cells.

The cytokine Tumor Necrosis Factor-α is critical to Estrogen Receptor positive breast cancer pathology, stimulating estrogen-biosynthesis pathways and preventing the differentiation of estrogen-producing fibroblasts. High concentrations of TNFα are detected in the tumor microenvironment, and infiltrating immune cells are thought to be a major source. This study identifies that TNFα is also a tumor-derived factor, expressed in ER+ tumour epithelial cells and regulated by 17-β-estradiol (E2).

Use of phage display to identify novel mineralocorticoid receptor-interacting proteins.

The mineralocorticoid receptor (MR) plays a central role in salt and water homeostasis via the kidney; however, inappropriate activation of the MR in the heart can lead to heart failure. A selective MR modulator that antagonizes MR signaling in the heart but not the kidney would provide the cardiovascular protection of current MR antagonists but allow for normal electrolyte balance. The development of such a pharmaceutical requires an understanding of coregulators and their tissue-selective interactions with the MR, which is currently limited by the small repertoire of MR coregulators described in the literature.

Transcriptional control of local estrogen formation by aromatase in the breast.

Aromatase is the critical enzyme that converts androgens to estrogens. It is frequently highly expressed in the tumour bearing breast of women diagnosed with estrogen receptor positive tumours, resulting in dramatically increased local estrogen production to drive tumour progression. Expression of aromatase is regulated primarily at the transcriptional level of its encoding gene CYP19A1, located on chromosome 15 of the human genome.

Conditional overexpression of liver receptor homolog-1 in female mouse mammary epithelium results in altered mammary morphogenesis via the induction of TGF-β.

Liver receptor homolog-1 (LRH-1) is an orphan nuclear receptor that belongs to the NR5A subgroup of nuclear receptors. LRH-1 induces key genes to regulate metabolic process, ovarian function, cancer cell proliferation, and steroidogenesis. In the breast, LRH-1 modulates and synergizes with endogenous estrogen signaling to promote breast cancer cell proliferation.

Endocrine disruption of the epigenome: a breast cancer link.

The heritable component of breast cancer accounts for only a small proportion of total incidences. Environmental and lifestyle factors are therefore considered to among the major influencing components increasing breast cancer risk. Endocrine-disrupting chemicals (EDCs) are ubiquitous in the environment.

Hepatic glucose intolerance precedes hepatic steatosis in the male aromatase knockout (ArKO) mouse.

Estrogens are known to play a role in modulating metabolic processes within the body. The Aromatase knockout (ArKO) mice have been shown to harbor factors of Metabolic syndrome with central adiposity, hyperinsulinemia and male-specific hepatic steatosis. To determine the effects of estrogen ablation and subsequent replacement in males on whole body glucose metabolism, three- and six-month-old male ArKO mice were subjected to whole body glucose, insulin and pyruvate tolerance tests and analyzed for ensuing metabolic changes in liver, adipose tissue, and skeletal muscle.

Distinct nuclear receptor expression in stroma adjacent to breast tumors.

The interaction between breast tumor epithelial and stromal cells is vital for initial and recurrent tumor growth. While breast cancer-associated stromal cells provide a favorable environment for proliferation and metastasis, the molecular mechanisms contributing to this process are not fully understood. Nuclear receptors (NRs) are intracellular transcription factors that directly regulate gene expression.

Oestradiol reduces liver receptor homolog-1 mRNA transcript stability in breast cancer cell lines.

The expression of orphan nuclear receptor Liver Receptor Homolog-1 (LRH-1) is elevated in breast cancer and promotes proliferation, migration and invasion in vitro. LRH-1 expression is regulated by oestrogen (E2), with LRH-1 mRNA transcript levels higher in oestrogen receptor α (ERα) positive (ER+) breast cancer cells compared to ER- cells. However, the presence of LRH-1 protein in ER- cells suggests discordance between mRNA transcript levels and protein expression.

Liver receptor homologue-1 expression in ovarian epithelial and granulosa cell tumours.

Granulosa cell tumours of the ovary (GCT) express aromatase and produce oestrogens. The ovarian-specific aromatase promoter (pII) is regulated by members of the group 5A nuclear receptor family, SF-1 and LRH-1. Since both SF-1 and LRH-1 are implicated in proliferation and cancer, we hypothesised that alteration in the expression of either or both receptors may be associated with GCT.

NFκB and MAPK signalling pathways mediate TNFα-induced Early Growth Response gene transcription leading to aromatase expression.

The Early Growth Response genes EGR2 and EGR3 play an important role in mediating TNFα induced aromatase expression via the adipose specific promoter PI.4. The upstream signalling pathway stimulated by TNFα to initiate this is unknown.

Origins and actions of tumor necrosis factor α in postmenopausal breast cancer.

Tumor necrosis factor α (TNFα) has many roles in both physiological and pathological states. Initially thought to cause necrosis of tumors, research has shown that in many tumor types, including breast cancer, TNFα contributes to growth and proliferation. The presence of TNFα-derived from the tumor and infiltrating immune cells-within a breast tumor microenvironment has been correlated with a more aggressive phenotype, and the postmenopausal ER+ subtype of breast cancers appears to strongly respond to its many pro-growth signaling functions.

Intracrine oestrogen production and action in breast cancer: an epigenetic focus.

Epigenome changes have been widely demonstrated to contribute to the initiation and progression of a vast array of cancers including breast cancer. The reversible process of many epigenetic modifications is thus an attractive feature for the development of novel therapeutic measures. In oestrogen receptor α (hereinafter referred to as ER) positive tumours, endocrine therapies have proven beneficial in patient care, particularly in postmenopausal women where two-thirds of tumours are oestrogen dependent.

Involvement of early growth response factors in TNFα-induced aromatase expression in breast adipose.

Expression of the oestrogen producing enzyme, aromatase, is regulated in a tissue-specific manner by its encoding gene CYP19A1. In post-menopausal women, the major site for oestrogen production in the breast is the adipose, where CYP19A1 transcription is driven by the distal promoter I.4 (PI.