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FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor 1 – 4 , but mechanisms regulating its binding to chromatin remain elusive. LSD1 (KDM1A) acts as a transcriptional repressor by demethylating mono/dimethylated histone H3 lysine 4 (H3K4me1/2) 5 , 6 , but also acts as a steroid hormone receptor coactivator through mechanisms that are unclear. Here we show, in prostate cancer cells, that LSD1 associates with FOXA1 and active enhancer markers, and that LSD1 inhibition globally disrupts FOXA1 chromatin binding. Mechanistically, we demonstrate that LSD1 positively regulates FOXA1 binding by demethylating lysine 270, adjacent to the wing2 region of the FOXA1 DNA-binding domain. Acting through FOXA1, LSD1 inhibition broadly disrupted androgen-receptor binding and its transcriptional output, and dramatically decreased prostate cancer growth alone and in synergy with androgen-receptor antagonist treatment in vivo. These mechanistic insights suggest new therapeutic strategies in steroid-driven cancers. LSD1 promotes FOXA1 chromatin binding by demethylating lysine 270 of FOXA1 in prostate cancer cells. LSD1 inhibition decreases growth of prostate cancer cells.

Testicular anti-Müllerian hormone (AMH) production is inhibited by androgens around pubertal onset, as observed under normal physiological conditions and in patients with precocious puberty. In agreement, AMH downregulation is absent in patients with androgen insensitivity. The molecular mechanisms underlying the negative regulation of AMH by androgens remain unknown. Our aim was to elucidate the mechanisms through which androgens downregulate AMH expression in the testis. A direct negative effect of androgens on the transcriptional activity of the AMH promoter was found using luciferase reporter assays in the mouse prepubertal Sertoli cell line SMAT1. A strong inhibition of AMH promoter activity was seen in the presence of both testosterone and DHT and of the androgen receptor. By site-directed mutagenesis and chromatin immunoprecipitation assays, we showed that androgen-mediated inhibition involved the binding sites for steroidogenic factor 1 (SF1) present in the proximal promoter of the AMH gene. In this study, we describe for the first time the mechanism behind AMH inhibition by androgens, as seen in physiological and pathological conditions in males. Inhibition of AMH promoter activity by androgens could be due to protein–protein interactions between the ligand-bound androgen receptor and SF1 or by blockage of SF1 binding to its sites on the AMH promoter. Summary Sentence Androgens act directly on prepubertal Sertoli cells to inhibit AMH promoter activity in the presence of the androgen receptor and intact SF1 sites.

FK506 binding protein 52 (FKBP52) (gene name FKBP4) is a 52 kDa protein that belongs to the FKBP family; it binds to the immunosuppressant FK506 and has proline isomerase activity. In addition to its FK domain‐containing peptidylprolyl isomerase activity, FKBP52 also acts as a cochaperone through the tetratricopeptide repeat domain that mediates binding to heat shock protein 90. Previous studies have reported that FKBP52 is associated with hormone‐dependent, stress‐related, and neurodegenerative diseases, revealing its diverse functions. In particular, the effects of FKBP52 on cancer have attracted considerable attention. FKBP52 promotes the growth of hormone‐dependent cancers by activating steroid hormone receptors. Recent studies have shown that the expression of FKBP52 is increased not only in steroid hormone‐dependent cancer cells but also in colorectal, lung, and liver cancers, revealing its diverse functions that contribute to cancer growth. This review summarizes reports related to hormone‐dependent cancer and cell proliferation in terms of the structure of FKBP52 and its function on interacting molecules. FK506 binding protein FKBP52 is associated with hormone‐dependent, stress‐related, and neurodegenerative diseases, revealing its diverse functions. In particular, FKBP52 promotes the growth of hormone‐dependent cancers by activating steroid hormone receptors.

Maternal stress and inflammation excesses can lead to adverse pregnancy outcomes and offspring development. We evaluated whether distinct prenatal stressors affect pregnancy, maternal and offspring outcomes, and uterine gene expression differently when combined than either alone. Long-Evans dams were exposed to psychological or/and (two-hit) immune stress (interleukin-1 beta [IL-1β]), on gestational days 12–18 and 17-delivery, respectively. Gestational length, maternal weight gain, glycaemia and corticosterone levels, offspring weight, and gender effects were recorded. Maternal and offspring uteri were collected at weaning and on postnatal day 160 correspondingly. Uterine expression of genes involved in local progesterone metabolism, neuroendocrine and immune systems were analyzed using quantitative real-time polymerase chain reaction. Maternal two-hit stress increased gestational length variation and the occurrence of adverse pregnancy outcomes while reducing gestational weight gain. Pup weight was negatively affected by prenatal stressors in a gender-specific way. In dams, IL-1β upregulated gene expression of neuroendocrine (Crh, Crhr1) and cytokine genes (Il1b, Il1rn, Il6, and Il10). Conversely, transcriptional patterns in offspring uteri were more variable with gene-specific up- or downregulation by each stressor separately, while exposure to both extensively reduced the expression of neuroendocrine (Hsd11b1), cytokine (Il1a, Il1rn, Il6), and IL-1 receptor genes. In conclusion, maternal stress affects physiological and molecular processes in dams and their offspring; two hits have different effects than single stressors. Outcomes appear generation-, gender-, and stressor-specific. Dampening of offspring uterine gene expression after exposure to multiple stressors could fit within the match/mismatch hypothesis of perinatal programming, with offspring preparing for a stressful life. Summary Sentence The combination of two distinct prenatal stressors, psychological and immune stress, induces adverse outcomes and differentially affects expression of genes related to progesterone metabolism, stress and the immune system in the rat uterus.

Cervical mucus produced by the endocervix plays an essential role as a hormonally induced regulator of female fertility. Cervical mucus fluctuates in both physical characteristics and in sperm penetrability in response to estrogens and progestogens. However, the mechanisms by which steroid hormones change mucus remains poorly understood. Current in vitro models have limited capability to study these questions as primary endocervical cells possess limited expansion potential, and immortalized cells lose in vivo characteristics such as steroid sensitivity. Here we overcome these limitations by establishing an in vitro primary endocervical cell culture model using conditionally reprogrammed cells (CRCs). CRC culture utilizes a Rho-kinase inhibitor and a fibroblast feeder layer to expand proliferative potential of epithelial cell types that have normally short in vitro life spans. In our studies, we produce CRC cultures using primary endocervical cells from adult female rhesus macaques (Macaca mulatta). We demonstrate that primary endocervical cells from the nonhuman primate can be robustly expanded using a CRC method, while retaining steroid receptor expression. Moreover, when removed from CRC conditions and switched to differentiation conditions, these cells are able to differentiate and produce mucus including MUC5B, the most prevalent mucin of the endocervix. We conclude that this method provides a promising in vitro platform for conducting mechanistic studies of cervical mucus regulation as well as for screening new therapeutic targets for fertility regulation and diseases of the endocervix. Summary sentence Conditionally reprogrammed macaque endocervical cells retain steroid receptor expression and produce mucus.

Epidemiological and experimental findings suggest that the development of gastric cancer (GC) is regulated by steroid hormones. In postmenopausal women and older men, the majority of steroid hormones are produced locally in peripheral tissue through the enzymatic conversion of steroid precursors. Therefore, using reverse transcription-quantitative polymerase chain reaction analysis, the mRNA expression of genes encoding steroidogenic enzymes, including steroid sulfatase (STS), hydroxy-delta-5-steroid dehydrogenase 3 beta- and steroid delta-isomerase 1 (HSD3B1), 17β-hydroxysteroid dehydrogenase type 7 and aromatase (CYP19A1), was investigated in primary tumoral and adjacent healthy gastric mucosa from 60 patients with GC. Furthermore, the mRNA levels for estrogen receptor α, estrogen receptor β (ESR2) and androgen receptor (AR), along with their coregulators, including proline, glutamate and leucine rich protein 1, CREB binding protein, nuclear receptor coactivator 1 (NCOA1), nuclear receptor corepressor 1 (NCOR1) and nuclear receptor subfamily 2 group F member 1 (NR2F1), were investigated. Additionally, the association between the mRNA expression of these genes and the clinicopathological features of patients with GC was examined. Significantly decreased levels of STS, HSD3B1, ESR2, AR, NCOA1 and NCOR1 mRNA, in addition to significantly increased levels of CYP19A1 mRNA were demonstrated in tumoral tissue samples compared with adjacent healthy gastric tissue samples. Deregulated expression of these genes in the analyzed tissue samples was associated with certain clinicopathological features of GC, such as age and localization of the tumor. The results of the current study suggest that all of the genes analyzed are expressed in tumoral and adjacent healthy gastric mucosa. In addition, the results indicate that abnormal expression of STS, ESR2, AR, NCOA1 and NCOR1 may serve a role in the development and progression of GC, and may be associated with specific clinicopathological features in patients with GC.

Steroid hormone receptors （SHRs） act in cell type- and gene-specific manner through interactions with coregulatory proteins to regulate numerous physiological and pathological processes at the level of gene regulation. Binding of steroid receptor modulator （SRM） ligand leads to allosteric changes in SHR to exert positive or negative effects on the expression of target genes. Due, in part, to the fact that current SRMs generally target ligand binding domain （LBD）/AF2 and neglect intrinsically disordered （ID） N-terminal domain （NTD）/AF1, clinically relevant SRMs lack selectivity and are also prone to the development of resistance over time. Therefore, to maximize the efficacy of SHR-based therapeutics, the possibility of developing unique modulators that act to control AF1 activity must be considered. Recent studies targeting androgen receptor＇s （AR＇s） ID AF1 domain for the castration-resistant prostate cancer has provided the possibility of therapeutically targeting ID NTD/AF1 surfaces by allosteric modulations to achieve desired effects. In this review article, we discuss how inter- and intra- molecular allosteric regulations controlled by AR＇s structural flexibility and dynamics particularly the ID NTD/AF1 is an emerging area of investigation, which could be exploited for drug development and therapeutic targeting of prostate cancer.

Purpose Adjuvant endocrine therapy (ET) is indicated in patients with steroid hormone receptor (HR)-positive breast cancer. The aim of this study was to evaluate the quality of HR determination and adjuvant endocrine treatment of breast cancer patients in a large cohort of more than 7000 women by analyzing data from a population-based regional cancer registry. Methods Data from the Clinical Cancer Registry Regensburg (Bavaria, Germany) were analyzed. Female patients with primary, nonmetastatic invasive breast cancer who were diagnosed between 2000 and 2012 ( n  = 7421) were included. HR-status was available in 97.4 % ( n  = 7229) of the patients. This data set ( n  = 7229) was used for subsequent statistical analyses. Results Since 2009, almost a complete rate of 99.6 % of analyzed HR-status was achieved. In sum, 85.8 % of the patients ( n  = 6199) were HR-positive, whereas 14.2 % ( n  = 1030) were HR-negative. Overall, 85.3 % ( n  = 5285) of HR-positive patients received ET either alone or in combination with chemotherapy (CHT) and/or trastuzumab. The majority of premenopausal patients received CHT plus ET (716 patients, 52.3 %). In postmenopausal patients, the most frequent systemic therapy was ET alone (2670 patients, 55.3 %). Best overall survival (OS) was found in HER2-/HR-positive patients receiving CHT plus ET plus trastuzumab (7-year OS rate of 97.2 % in premenopausal patients versus 86.9 % in postmenopausal patients). Premenopausal patients had a reduced benefit from additional CHT than postmenopausal patients. Premenopausal patients receiving only ET had a 7-year OS rate of 95.3 % compared to 92.7 % of patients receiving CHT plus ET. In contrast, postmenopausal patients treated with CHT plus ET had a 7-year OS rate of 84.0 % in comparison with those patients receiving only ET with a 7-year OS rate of 81.7 %. Conclusions Analysis of HR in patients with early breast cancer achieved a very high quality in recent years. The vast majority of HR-positive patients received ET, and this guideline-adherent use improved OS. Inverse effects of the CHT plus ET combination in premenopausal versus postmenopausal patients and a still existing minority of patients not receiving guideline-adherent treatment should be further investigated in future studies.

Oestradiol establishes neural sex differences in many vertebrates 1 – 3 and modulates mood, behaviour and energy balance in adulthood 4 – 8 . In the canonical pathway, oestradiol exerts its effects through the transcription factor oestrogen receptor-α (ERα) 9 . Although ERα has been extensively characterized in breast cancer, the neuronal targets of ERα, and their involvement in brain sex differences, remain largely unknown. Here we generate a comprehensive map of genomic ERα-binding sites in a sexually dimorphic neural circuit that mediates social behaviours. We conclude that ERα orchestrates sexual differentiation of the mouse brain through two mechanisms: establishing two male-biased neuron types and activating a sustained male-biased gene expression program. Collectively, our findings reveal that sex differences in gene expression are defined by hormonal activation of neuronal steroid receptors. The molecular targets we identify may underlie the effects of oestradiol on brain development, behaviour and disease. A study maps neuronal genomic targets of oestrogen receptor-α and shows how they coordinate brain sexual differentiation, concluding that the genome remains responsive to hormonal changes after structural dimorphisms have been established.

Most proteins assemble into multisubunit complexes 1 . The persistence of these complexes across evolutionary time is usually explained as the result of natural selection for functional properties that depend on multimerization, such as intersubunit allostery or the capacity to do mechanical work 2 . In many complexes, however, multimerization does not enable any known function 3 . An alternative explanation is that multimers could become entrenched if substitutions accumulate that are neutral in multimers but deleterious in monomers; purifying selection would then prevent reversion to the unassembled form, even if assembly per se does not enhance biological function 3 – 7 . Here we show that a hydrophobic mutational ratchet systematically entrenches molecular complexes. By applying ancestral protein reconstruction and biochemical assays to the evolution of steroid hormone receptors, we show that an ancient hydrophobic interface, conserved for hundreds of millions of years, is entrenched because exposure of this interface to solvent reduces protein stability and causes aggregation, even though the interface makes no detectable contribution to function. Using structural bioinformatics, we show that a universal mutational propensity drives sites that are buried in multimeric interfaces to accumulate hydrophobic substitutions to levels that are not tolerated in monomers. In a database of hundreds of families of multimers, most show signatures of long-term hydrophobic entrenchment. It is therefore likely that many protein complexes persist because a simple ratchet-like mechanism entrenches them across evolutionary time, even when they are functionally gratuitous. Accumulation of hydrophobic residues at the interface between monomers may favour the maintenance of multimeric protein states during evolution, even if multimerization confers no functional advantage.