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Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer.

ABSTRACT: Male breast cancer (MBC) is rare and poorly characterized. Like the female counterpart, most MBCs are hormonally driven, but relapse after hormonal treatment is also noted. The pan-hormonal action of steroid hormonal receptors, including estrogen receptor alpha (ER?), androgen receptor (AR), progesterone receptor (PR), and glucocorticoid receptor (GR) in this understudied tumor type remains wholly unexamined. This study reveals genomic cross-talk of steroid hormone receptor action and interplay in human tumors, here in the context of MBC, in relation to the female disease and patient outcome. Here we report the characterization of human breast tumors of both genders for cistromic make-up of hormonal regulation in human tumors, revealing genome-wide chromatin binding landscapes of ER?, AR, PR, GR, FOXA1, and GATA3 and enhancer-enriched histone mark H3K4me1. We integrate these data with transcriptomics to reveal gender-selective and genomic location-specific hormone receptor actions, which associate with survival in MBC patients.

SUBMITTER: Severson TM

PROVIDER: S-EPMC5797120 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer

Project description:Male breast cancer (MBC) is rare and poorly characterized. Like the female counterpart, most MBCs are hormonally driven, but resistance to hormonal treatment is common. We use transcriptomics to reveal gender-selective and genomic location-specific hormone receptor actions, which associated with survival in MBC patients.

2018-02-02 | GSE104730 | GEO

Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer

Project description:Male breast cancer (MBC) is rare and poorly characterized. Like the female counterpart, most MBCs are hormonally driven, but resistance to hormonal treatment is common. The pan-hormonal action of steroid hormonal receptors including Estrogen Receptor alpha (ERα), Androgen Receptor (AR), Progesterone Receptor (PR) and Glucocorticoid Receptor (GR) in this understudied tumor type remains wholly unexamined. This pioneering study reveals genomic cross-talk of steroid hormone receptor action and interplay in human tumors, here in the context of MBC, in relation to patient outcome. Using chromatin immunoprecipitation coupled with massively-parallel sequencing (ChIP-seq), we characterized human MBCs for epigenetic make-up of hormonal regulation in human tumors, revealing genome-wide chromatin binding landscapes of ERα, AR, PR and GR, along with pioneer factor FOXA1 and enhancer-enriched histone mark H3K4me1. These data were integrated with transcriptomics analyses to reveal gender-selective and genomic location-specific hormone receptor action, that are associated with survival in MBC patients.

2018-02-02 | GSE104399 | GEO

Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer

Project description:Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer

| PRJNA413693 | ENA

Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer

Project description:Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer

| PRJNA412535 | ENA

A male-specific steroid hormone controls female reproductive biology in the malaria mosquito

Project description:Insects, unlike vertebrates, are generally believed to lack steroid hormones with functions predominantly associated with adult male biology. In the malaria mosquito Anopheles gambiae, the ecdysteroid 20-hydroxyecdysone (20E) appears to both control egg development in females and induce mating refractoriness and oviposition when sexually transferred by males. Here we show that these sex-specific functions are instead carried out by distinct steroids. We identify a male-specific oxidized form of 20E (3D20E) that upon sexual transfer switches off female mating receptivity, ensuring male paternity. Endogenous female 20E does not induce mating refractoriness, while it triggers oviposition in mated females when expression of a 20E-inhibiting kinase is repressed. 3D20E and 20E have different downstream targets, with 3D20E inducing expression of a tolerance factor that preserves female fitness during Plasmodium infection. The evolution of this male steroid has therefore not only shaped the mating biology of An. gambiae, but also impacted malaria transmission.

2022-04-21 | PXD032157 | Pride

Steroid Hormone Receptor Positive Breast Cancer Patient-Derived Xenografts.

Project description:The vast majority of breast cancers are positive for estrogen receptor (ER) and depend on estrogens for growth. These tumors are treated with a variety of ER-targeted endocrine therapies, although eventual resistance remains a major clinical problem. Other steroid hormone receptors such as progesterone receptor (PR) and androgen receptor (AR) are emerging as additional prospective targets in breast cancer. The fundamental mechanism of action of these steroid receptors in gene regulation has been defined mainly by several breast cancer cell lines that were established in the late 1970s. More recently, breast cancer patient-derived xenografts (PDX) have been developed by multiple groups at institutions in several countries. These new models capture the large degree of heterogeneity between patients and within tumors and promise to advance our understanding of steroid hormone receptor positive breast cancer and endocrine resistance. Unfortunately, steroid hormone receptor positive breast cancers are much more difficult than their receptor negative counterparts to establish into sustainable PDX. Herein we discuss the derivation of steroid hormone receptor positive breast cancer PDX, several pitfalls in their genesis, and their utility in preclinical and translational steroid hormone receptor research.

| S-EPMC5291783 | biostudies-literature

The steroid hormone ecdysone functions with intrinsic chromatin remodeling factors to control female germline stem cells in Drosophila.

Project description:Steroid hormones are known systemic regulators of multiple normal and cancerous tissues; however, whether or how they impact the fate and function of adult stem cells is unclear. In the Drosophila ovary, insulin signals modulate the proliferation and self-renewal of germline stem cells (GSCs), yet despite evidence that additional systemic factors control GSC activity, these have remained largely unknown. Here, we report that ecdysone, a steroid hormone structurally related to mammalian sex steroids, directly regulates adult GSC proliferation and self-renewal independently of insulin signaling. Ecdysone controls GSCs through a functional interaction with the chromatin remodeling factors ISWI, an intrinsic epigenetic factor required for GSC fate and activity, and Nurf301, the largest subunit of the ISWI-containing NURF chromatin remodeling complex. Our findings support a link between systemic steroid hormones and the intrinsic chromatin remodeling machinery as a potential mechanism to promote broad transcriptional programs required for adult stem cell self-renewal.

| S-EPMC3292427 | biostudies-literature

The binding of 3H-labelled oestradiol- and progesterone-receptor complexes to hypothalamic chromatin of male and female sheep.

Project description:Chromatin isolated from hypothalamic nuclei of sexually mature entire male and female sheep was linked to cellulose in u.v. light. The saturation binding of 3H-labelled oestrogen- and progesterone-receptor complexes, prepared by (NH4)2SO4 precipitation from the 105000g supernatant of hypothalamic cytosol, was then measured in vitro in 0.15m-KCl. Saturation binding was also measured after extraction of histones and masking acidic proteins. Salt + urea was observed to be more effective than guanidine hydrochloride in unmasking receptor acceptor sites, and the binding of labelled receptor complexes to dehistonized unmasked chromatin was shown to be largely resistant to 0.4m-KCl extraction. Whereas extents of receptor-complex binding were similar to published values for comparable preparations of hen oviduct chromatin, no sex-related difference was observed. However, binding of progesterone-receptor to chromatin was greater than that of oestradiol-receptor. Binding also increased more after removal of histones and masking acidic proteins, suggesting the presence of a greater number of progesterone-receptor acceptor sites in hypothalamic chromatin than of estradiol-receptor acceptor sites. The failure to demonstrate a sex-related difference in oestradiol-receptor binding to hypothalamic chromatin in vitro is discussed.

| S-EPMC1186311 | biostudies-other

Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action.

Project description:Biologically active steroids are transported in the blood by albumin, sex hormone-binding globulin (SHBG), and corticosteroid-binding globulin (CBG). These plasma proteins also regulate the non-protein-bound or 'free' fractions of circulating steroid hormones that are considered to be biologically active; as such, they can be viewed as the 'primary gatekeepers of steroid action'. Albumin binds steroids with limited specificity and low affinity, but its high concentration in blood buffers major fluctuations in steroid concentrations and their free fractions. By contrast, SHBG and CBG play much more dynamic roles in controlling steroid access to target tissues and cells. They bind steroids with high (~nM) affinity and specificity, with SHBG binding androgens and estrogens and CBG binding glucocorticoids and progesterone. Both are glycoproteins that are structurally unrelated, and they function in different ways that extend beyond their transportation or buffering functions in the blood. Plasma SHBG and CBG production by the liver varies during development and different physiological or pathophysiological conditions, and abnormalities in the plasma levels of SHBG and CBG or their abilities to bind steroids are associated with a variety of pathologies. Understanding how the unique structures of SHBG and CBG determine their specialized functions, how changes in their plasma levels are controlled, and how they function outside the blood circulation provides insight into how they control the freedom of steroids to act in health and disease.

| S-EPMC5064763 | biostudies-literature

DNA Sequence Constraints Define Functionally Active Steroid Nuclear Receptor Binding Sites in Chromatin.

Project description:Gene regulatory programs are encoded in the sequence of the DNA. Since the completion of the Human Genome Project, millions of gene regulatory elements have been identified in the human genome. Understanding how each of those sites functionally contributes to gene regulation, however, remains a challenge for nearly every field of biology. Transcription factors influence cell function by interpreting information contained within cis-regulatory elements in chromatin. Whereas chromatin immunoprecipitation-sequencing has been used to identify and map transcription factor-DNA interactions, it has been difficult to assign functionality to the binding sites identified. Thus, in this study, we probed the transcriptional activity, DNA-binding competence, and functional activity of select nuclear receptor mutants in cellular and animal model systems and used this information to define the sequence constraints of functional steroid nuclear receptor cis-regulatory elements. Analysis of the architecture within sNR chromatin interacting sites revealed that only a small fraction of all sNR chromatin-interacting events is associated with transcriptional output and that this functionality is restricted to elements that vary from the consensus palindromic elements by one or two nucleotides. These findings define the transcriptional grammar necessary to predict functionality from regulatory sequences, with a multitude of future implications.

| S-EPMC5659708 | biostudies-literature

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