Estrogen receptor beta expression and role in cancers.

Estrogen drives the growth of some cancers, such as breast cancer, via estrogen receptor alpha (ERα). Estrogen also activates ERß, but whether ERß is expressed and has a role in different cancers is debated. The use of nonspecific antibodies has contributed to the confusion, and this review delves into ERß's controversial role in cancer and focuses on tumor expression that can be supported by non-antibody-dependent assays. We discuss its expression at the transcript level and focus on its potential role in lymphoma, granulosa cell tumors, testicular, and adrenal cancers, emphasizing recent findings and the complexities that necessitate further research.

Ovarian ERß cistrome and transcriptome reveal chromatin interaction with LRH-1.

BACKGROUND: Estrogen receptor beta (ERß, Esr2) plays a pivotal role in folliculogenesis and ovulation, yet its exact mechanism of action is mainly uncharacterized. RESULTS: We here performed ERß ChIP-sequencing of mouse ovaries followed by complementary RNA-sequencing of wild-type and ERß knockout ovaries. By integrating the ERß cistrome and transcriptome, we identified its direct target genes and enriched biological functions in the ovary. This demonstrated its strong impact on genes regulating organism development, cell migration, lipid metabolism, response to hypoxia, and response to estrogen. Cell-type deconvolution analysis of the bulk RNA-seq data revealed a decrease in luteal cells and an increased proportion of theca cells and a specific type of cumulus cells upon ERß loss. Moreover, we identified a significant overlap with the gene regulatory network of liver receptor homolog 1 (LRH-1, Nr5a2) and showed that ERß and LRH-1 extensively bound to the same chromatin locations in granulosa cells. Using ChIP-reChIP, we corroborated simultaneous ERß and LRH-1 co-binding at the ERß-repressed gene Greb1 but not at the ERß-upregulated genes Cyp11a1 and Fkbp5. Transactivation assay experimentation further showed that ERß and LRH-1 can inhibit their respective transcriptional activity at classical response elements. CONCLUSIONS: By characterizing the genome-wide endogenous ERß chromatin binding, gene regulations, and extensive crosstalk between ERß and LRH-1, along with experimental corroborations, our data offer genome-wide mechanistic underpinnings of ovarian physiology and fertility.

High-fat diet and estrogen modulate the gut microbiota in a sex-dependent manner in mice.

A high-fat diet can lead to gut microbiota dysbiosis, chronic intestinal inflammation, and metabolic syndrome. Notably, resulting phenotypes, such as glucose and insulin levels, colonic crypt cell proliferation, and macrophage infiltration, exhibit sex differences, and females are less affected. This is, in part, attributed to sex hormones. To investigate if there are sex differences in the microbiota and if estrogenic ligands can attenuate high-fat diet-induced dysbiosis, we used whole-genome shotgun sequencing to characterize the impact of diet, sex, and estrogenic ligands on the microbial composition of the cecal content of mice. We here report clear host sex differences along with remarkably sex-dependent responses to high-fat diet. Females, specifically, exhibited increased abundance of Blautia hansenii, and its levels correlated negatively with insulin levels in both sexes. Estrogen treatment had a modest impact on the microbiota diversity but altered a few important species in males. This included Collinsella aerofaciens F, which we show correlated with colonic macrophage infiltration. In conclusion, male and female mice exhibit clear differences in their cecal microbial composition and in how diet and estrogens impact the composition. Further, specific microbial strains are significantly correlated with metabolic parameters.

SETD7 Expression Is Associated with Breast Cancer Survival Outcomes for Specific Molecular Subtypes: A Systematic Analysis of Publicly Available Datasets.

SETD7 is a lysine N-methyltransferase that targets many proteins important in breast cancer (BC). However, its role and clinical significance remain unclear. Here, we used online tools and multiple public datasets to explore the predictive potential of SETD7 expression (high or low quartile) considering BC subtype, grade, stage, and therapy. We also investigated overrepresented biological processes associated with its expression using TCGA-BRCA data. SETD7 expression was highest in the Her2 (ERBB2)-enriched molecular subtype and lowest in the basal-like subtype. For the basal-like subtype specifically, higher SETD7 was consistently correlated with worse recurrence-free survival (p < 0.009). High SETD7-expressing tumours further exhibited a higher rate of ERBB2 mutation (20% vs. 5%) along with a poorer response to anti-Her2 therapy. Overall, high SETD7-expressing tumours showed higher stromal and lower immune scores. This was specifically related to higher counts of cancer-associated fibroblasts and endothelial cells, but lower B and T cell signatures, especially in the luminal A subtype. Genes significantly associated with SETD7 expression were accordingly overrepresented in immune response processes, with distinct subtype characteristics. We conclude that the prognostic value of SETD7 depends on the BC subtype and that SETD7 may be further explored as a potential treatment-predictive marker for immune checkpoint inhibitors.

ERα and ERß Homodimers in the Same Cellular Context Regulate Distinct Transcriptomes and Functions.

The two estrogen receptors ERα and ERß are nuclear receptors that bind estrogen (E2) and function as ligand-inducible transcription factors. They are homologues and can form dimers with each other and bind to the same estrogen-response element motifs in the DNA. ERα drives breast cancer growth whereas ERß has been reported to be anti-proliferative. However, they are rarely expressed in the same cells, and it is not fully investigated to which extent their functions are different because of inherent differences or because of different cellular context. To dissect their similarities and differences, we here generated a novel estrogen-dependent cell model where ERα homodimers can be directly compared to ERß homodimers within the identical cellular context. By using CRISPR-cas9 to delete ERα in breast cancer MCF7 cells with Tet-Off-inducible ERß expression, we generated MCF7 cells that express ERß but not ERα. MCF7 (ERß only) cells exhibited regulation of estrogen-responsive targets in a ligand-dependent manner. We demonstrated that either ER was required for MCF7 proliferation, but while E2 increased proliferation via ERα, it reduced proliferation through a G2/M arrest via ERß. The two ERs also impacted migration differently. In absence of ligand, ERß increased migration, but upon E2 treatment, ERß reduced migration. E2 via ERα, on the other hand, had no significant impact on migration. RNA sequencing revealed that E2 regulated a transcriptome of around 800 genes via each receptor, but over half were specific for either ERα or ERß (417 and 503 genes, respectively). Functional gene ontology enrichment analysis reinforced that E2 regulated cell proliferation in opposite directions depending on the ER, and that ERß specifically impacted extracellular matrix organization. We corroborated that ERß bound to cis-regulatory chromatin of its unique proposed migration-related direct targets ANXA9 and TFAP2C. In conclusion, we demonstrate that within the same cellular context, the two ERs regulate cell proliferation in the opposite manner, impact migration differently, and each receptor also regulates a distinct set of target genes in response to E2. The developed cell model provides a novel and valuable resource to further complement the mechanistic understanding of the two different ER isoforms.