Endocrine Abstracts

Androgens initially drive prostate tumour growth. Although in advanced disease there is no longer dependence on circulating androgens, the androgen receptor (AR) remains a key driver of this lethal stage thus new ways to inhibit its activity are required. MicroRNAs play vital roles in prostate cancer (PCa) development, progression and metastasis. Previous studies have examined microRNAs dysregulated in PCa, and also identified androgen-regulated microRNAs. We approached microR...

The balance of androgen and estrogen hormone activity determines the degree of breast development in males and females. A predominance of androgen action impedes whereas a predominance of estrogen action promotes breast development. This sex hormone antagonism is mechanistically mediated by androgen and estrogen receptors (AR, ER). The alpha form of ER (ERα) is required for normal breast development and is the driving oncogene in the majority of breast cancers. The AR is ...

Transcriptional enhancers, which function as nucleation sites for the assembly of transcription-regulating complexes across the genome, drive cell type-specific patterns of gene expression that underlie the distinct biological properties of different cell types. Although many features of active enhancers (e.g., H3K4me1, H3K27ac, enrichment of p300/CBP and Mediator, and enhancer RNA production) have been defined by genomic assays, the roles of these features in ERα enhance...

Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance is common. Through ChIP-seq analyses, we presviously identified direct target genes of ERα acting in complex with SRC1, SRC2 or SRC3 (Zwart et al., 2011 EMBO J). Only the 111 genes there were under direct control of ERα in conjunction with SRC3 (but not the other two p160s) predicted...

Glucocorticoids (GCs) act through the glucocorticoid receptor (GR) to regulate immunity, energy metabolism, and tissue repair. The inactive GR is held in the cytoplasm in a multi-protein complex, which upon ligand binding undergoes a conformational change. Activated GR translocates to the nucleus to regulate gene expression (over hours), but some effects occur more rapidly. GCs inhibit cell migration through an uncertain mechanism. We now show a very rapid effect, and surprisi...

The human endometrium is a complex multicellular tissue the prime function of which is to provide a receptive environment during a fertile cycle. The tissue responds to steroid hormones exhibiting dynamic cyclical regeneration, angiogenesis, differentiation (decidualisation) and inflammation. In the absence of an embryo the inner surface is shed and repaired without scarring (menstruation). The endometrium exhitbits spatial and temporal expression of androgen receptors (AR) in...

The androgen receptor (AR) functions as a master transcriptional regulator of prostate tissue homeostasis. This master transcriptional regulator function is maintained in prostate cancer. Therefore, prostate cancer is an androgen-dependent disease and suppression of AR transcriptional activity with androgen deprivation therapy (ADT) is an effective systemic therapy. However, development of therapy resistance and transition to castration resistant prostate cancer (CRPC) represe...

Global knockout models of the androgen receptor (ARKO) illustrates the many roles androgens and their receptor have in the development of male reproductive organs and the gender differences in many features like the musculoskeletal system. However, neither the global ARKO nor orchidectomy models discriminate between direct and indirect effects of androgens. To determine direct and indirect effects of androgens on muscle, we developed a muscle-specific ARKO (called satARKO for ...

Progesterone receptors (PR) are long recognized to suppress estrogen receptor (ER) mediated transcription in breast cancers. However, a mechanistic basis for this repression has been lacking. Recent reports indicate this occurs, in part, through global repositioning of ER on chromatin in the presence of selective PR modulators (SPRMS), both agonists and antagonists [1, 2]. The goal of our studies was to further understand the mechanisms by which PR impacts estrogen-dependent g...

In normal physiology, glucocorticoid receptor (GR) activation regulates cell type-dependent genes whose products influence metabolism, inflammation, cell cycle and apoptosis/cell survival pathways. Synthetic GR agonists, or glucocorticoids (GCs), are often used to treat hematologic malignancies because of GR’s ability to induce proapoptotic gene expression, inhibit nuclear factor–κB, and induce cell cycle arrest. In contrast, recent examination of GR expression ...

The human genome is over 2 meters in length, which has to be folded in micrometer-sized nuclear space for proper functions. Although most of our understandings in the human genome are based on linear explanations, it has been speculated that the three-dimensional (3D) and high-order organization of the genome must play important roles in framing the mechanisms of nuclear process such as transcription regulation. Recent advance in 3D genome mapping technologies and sophisticate...

Male fertility is controlled by complex interactions between hypothalamus, pituitary, and testis. The major functions of the testis include production of spermatozoa and synthesis of hormones. Testosterone is produced by the testicular Leydig cells and ensures male fertility. Testosterone is involved in the development of gonad, the attainment of puberty, the maintenance of secondary sexual characteristics as well as in spermatogenesis process. Many studies have highlighted th...

The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumour evolution is poorly understood. Phenotypic divergence can be achieved via the inheritance of alternative transcriptional programs. Cell-type specific transcription is maintained through the activation of epigenetically-defined regulatory regions including promoters and enhancers. In this work, we annotated the epigenome of 47 primary and metastatic oestrogen-receptor (ERα)-positive br...

Localized transitions in chromatin structure accompany nuclear receptor binding events in mammalian cells. These remodeling processes are critical to determine the binding landscape for steroid receptors (SRs) in cancer cells. Multiple reports indicate that steroid receptors (ER, GR, AR, PR) can regulate the binding patterns for each other, particularly during cancer progression. Elucidation of the mechanisms by which these ‘chromatin opening’ processes occur is cent...