Estrogen receptor β (ERβ) is activated in the prostate by 5α-androstane-3β,17β-diol (3β-Adiol) where it exerts antiproliferative activity. The proliferative action of the androgen receptor is activated by 5α-dihydrotestosterone (DHT). Thus, prostate growth is governed by the balance between androgen receptor and ERβ activation. 3β-Adiol is a high-affinity ligand and agonist of ERβ and is derived from DHT by 3-keto reductase/3β-hydroxysteroid dehydrogenase enzymes. Here, we demonstrate that, when it is expressed in living cells containing an estrogen response element-luciferase reporter, 17β-hydroxysteroid dehydrogenase type 6 (17βHSD6) converts the androgen DHT to the estrogen 3β-Adiol, and this leads to activation of the ERβ reporter. This conversion of DHT occurs at concentrations that are in the physiological range of this hormone in the prostate. Immunohistochemical analysis revealed that 17βHSD6 is expressed in ERβ-positive epithelial cells of the human prostate and that, in prostate cancers of Gleason grade higher than 3, both ERβ and 17βHSD6 are undetectable. Both proteins were present in benign prostatic hyperplasia samples. These observations reveal that formation of 3β-Adiol via 17βHSD6 from DHT is an important growth regulatory pathway that is lost in prostate cancer.HSD17B6 | short-chain dehydrogenase | steroid metabolism | prereceptor regulation | intracrinology E strogen receptor β (ERβ) is a member of the nuclear receptor superfamily of transcription factors (1). ERβ is activated by its endogenous ligands estradiol-17β (E2) and 5α-androstane-3β,17β-diol (3β-Adiol). Activated ERβ is known to antagonize the proliferative actions of ERα (2-4). It has been shown that, in the prostate, 3β-Adiol is the physiological ligand of ERβ (2). This notion is supported by the fact that the intraprostatic 3β-Adiol level (10 nM) is 100-fold higher than that of E2 (0.1 nM) (5). 3β-Adiol is a metabolite of the androgen receptor (AR) agonist 5α-dihydrotestosterone (DHT).In vitro experiments using membrane preparations or purified enzymes have demonstrated that 3β-Adiol can be formed from DHT in two ways: (i) directly by 3-keto reduction of DHT to 3β-Adiol or (ii) by a two-enzyme process that entails a 3-keto reduction to 3α-Adiol followed by 3α-to 3β-hydroxysteroid epimerization.The most likely candidate enzyme for direct reduction is AKR1C1, a member of the aldo-keto reductase (AKR) family (6, 7). This cytosolic enzyme predominantly catalyzes the conversion of DHT to 3β-Adiol (8). A candidate for the first step in the twoenzyme pathway is AKR1C2, which converts DHT to 3α-Adiol (9). The mRNAs for both enzymes have been quantified in the human prostate by quantitative PCR (10); however, their cell type-specific protein expression in the prostate has not been reported.The epimerase reaction has been shown to be catalyzed by 17β-hydroxysteroid dehydrogenase type 6 (17βHSD6) (11, 12), also termed retinol dehydrogenase-like 3α-hydroxysteroid dehydrogenase (13,14). 17βHSD6 is a microsomal enzyme that belongs to the short-ch...

Hereditary, hormonal, and behavioral factors contribute to the development of breast cancer. Alcohol consumption is a modifiable behavior that is linked to increased breast cancer risks and is associated with the development of hormone-dependent breast cancers as well as disease progression and recurrence following endocrine treatment. In this study we examined the molecular mechanisms of action of alcohol by applying molecular, genetic, and genomic approaches in characterizing its effects on estrogen receptor (ER)-positive breast cancer cells. Treatments with alcohol promoted cell proliferation, increased growth factor signaling, and up-regulated the transcription of the ER target gene GREB1 but not the canonical target TFF1/pS2. Microarray analysis following alcohol treatment identified a large number of alcohol-responsive genes, including those which function in apoptotic and cell proliferation pathways. Furthermore, expression profiles of the responsive gene sets in tumors were strongly associated with clinical outcomes in patients who received endocrine therapy. Correspondingly, alcohol treatment attenuated the anti-proliferative effects of the endocrine therapeutic drug tamoxifen in ER-positive breast cancer cells. To determine the contribution and functions of responsive genes, their differential expression in tumors were assessed between outcome groups. The proto-oncogene BRAF was identified as a novel alcohol- and estrogen-induced gene that showed higher expression in patients with poor outcomes. Knock-down of BRAF, moreover, prevented the proliferation of breast cancer cells. These findings not only highlight the mechanistic basis of the effects of alcohol on breast cancer cells and increased risks for disease incidents and recurrence, but may facilitate the discovery and characterization of novel oncogenic pathways and markers in breast cancer research and therapeutics.

Background: The kidneys efficiently filter waste products while retaining serum proteins in the circulation. However, numerous diseases compromise this barrier function, resulting in spillage of serum proteins into the urine (proteinuria). Some studies of glomerular filtration suggest that tubules may be physiologically exposed to nephrotic-range protein levels. Therefore, whether serum components can directly injure the downstream tubular portions of the kidney, which in turn can lead to inflammation and fibrosis, remains controversial. Methods: We tested the effects of serum protein exposure in human kidney tubule microphysiologic systems (MPS) and with orthogonal epigenomic approaches. Animal models cannot directly assess the effect of serum components on tubules. Results: Serum, but not its major protein component albumin, induced tubular injury and secretion of proinflammatory cytokines. Epigenomic comparison of serum-injured tubules and intact kidney tissue revealed canonical stress-inducible regulation of injury-induced genes. Concordant transcriptional changes in microdissected tubulointerstitium were also observed in an independent cohort of patients with proteinuric kidney disease. Conclusions: Our results demonstrate a causal role for serum proteins in tubular injury and identify regulatory mechanisms and novel pathways for intervention.

Extracellular matrix (ECM)-induced β1-integrin-FAK signaling promotes cell attachment, survival, and migration of cancer cells in a distant organ so as to enable cancer metastasis. However, mechanisms governing activation of the β1-integrin-FAK signaling remain incompletely understood. Here, we report that vasodilator-stimulated phosphoprotein (VASP), an actin binding protein, is required for ECM–mediated β1-integrin-FAK-YAP1/TAZ signaling in gastrointestinal (GI) cancer cells and their liver metastasis. In patient-derived samples, VASP is upregulated in 53 of 63 colorectal cancers and 43 of 53 pancreatic ductal adenocarcinomas and high VASP levels correlate with liver metastasis and reduced patient survival. In a Matrigel-based 3-dimensional (3D) culture model, short hairpin RNA (shRNA)–mediated VASP knockdown in colorectal cancer cells (KM12L4, HCT116, and HT29) and pancreatic cancer cells (L3.6 and MIA PaCa-1) suppresses the growth of 3D cancer spheroids. Mechanistic studies reveal that VASP knockdown suppresses FAK phosphorylation and YAP1/TAZ protein levels, but not Akt or Erk-related pathways and that YAP1/TAZ proteins are enhanced by the β1-integrin-FAK signaling. Additionally, VASP regulates the β1-integrin-FAK-YAP1/TAZ signaling by at least two mechanisms: (1) promoting ECM-mediated β1-integrin activation and (2) regulating YAP1/TAZ dephosphorylation at downstream of RhoA to enhance the stability of YAP1/TAZ proteins. In agreement with these, preclinical studies with two experimental liver metastasis mouse models demonstrate that VASP knockdown suppresses GI cancer liver metastasis, β1-integrin activation, and YAP1/TAZ levels of metastatic cancer cells. Together, our data support VASP as a treatment target for liver metastasis of colorectal and pancreatic cancers.

The coronavirus disease 2019 (COVID-19) has caused many different complications including immunerelated conditions. Hereby, we report a case of a possible association between COVID-19 infection and de novo anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis presenting with severe pulmonary-renal syndrome as a rare complication of COVID-19 infection.We had a 53-year-old male patient who was admitted for a severe COVID-19 pneumonia complicated by septic shock and acute respiratory distress syndrome. He responded to the standard treatments and was discharged. Four months later, he was admitted with a severe acute pulmonary-renal syndrome (severe acute on chronic kidney failure with active sediment and proteinuria, and diffuse alveolar hemorrhage (DAH) requiring mechanical ventilation). Kidney biopsy confirmed pauci-immune fibro-cellular crescentic glomerulonephritis on top of glomerular sclerosis. Perinuclear-ANCA and anti-myeloperoxidase antibody came back positive. Pulse steroids and cyclophosphamide were administered. Given the chronicity of the kidney lesions, the kidney function did not improve significantly, and the patient became dialysis dependent; however, respiratory status responded dramatically, and he was discharged on room air. In conclusion, although COVID-19 infection can mimic ANCA-associated vasculitis (AAV), the growing number of case reports along with our report shows the need for awareness of a potential link between COVID-19 infection and AAV which would dramatically change the treatment strategy.

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The renal medulla is a specialized region of the kidney with important homeostatic functions. It has also been implicated in genetic and developmental disorders and ischemic and drug-induced injuries. Despite its role in kidney function and disease, the medulla's baseline gene expression and epigenomic signatures have not been well described in the adult human kidney. Here we generate and analyze gene expression (RNA-seq), chromatin accessibility (ATAC-seq) and chromatin conformation (Hi-C) data from adult human kidney cortex and medulla. Using data from our carefully annotated specimens, we assign samples in the larger public GTEx database to cortex and medulla, thereby identifying several misassignments and extracting meaningful medullary gene expression signatures. Using integrated analysis of gene expression, chromatin accessibility and conformation profiles, we reveal insights into medulla development and function. Our datasets will also provide a valuable resource for researchers in the GWAS community for functional annotation of genetic variants.

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