Steroid Hormones and Receptors in Health and Disease

Field: Biochemistry, Genetics and Molecular Biology (Life Sciences)

Steroid hormone effects have been reported for almost 140 years.1-3 In the past 50 years research has led to the discovery of steroid hormone receptors that act via both genomic and nongenomic ("rapid") mechanisms. Steroids are involved in physiology and disease, mediating endocrine, cardiovascular, and reproductive functions and playing a role in cancer, neurological, metabolic, renal, and cardiovascular diseases.4-7 Over the past decades, both the Federation of American Societies for Experimental Biology (FASEB) and the International Committee on Rapid Responses to Steroid Hormones (RRSH) have held meetings presenting the newest science on steroid hormone biology and receptor signaling8-26 (Tables 1 and 2). Previously, both FASEB8-14 and RRSH15-26 organized their own conferences, usually in alternating years, and in 2018, decided to organize their first joint conference to be held in the United States. Initially, the organizers of this joint conference (the authors of this manuscript) had selected West Palm Beach, FL, as the venue for the conference, which was to be held July 12-17, 2020. However, when the global coronavirus disease 2019 (COVID-19) pandemic hit earlier that year, plans were put on hold. Hoping for early control of the pandemic, the organizers prepared for a 4-day in-person meeting to be held in Puerto Rico, USA. However, as COVID-19 continued to be a global health concern, challenging societies, scientists, and science around the world, in late 2020, the organizers took the decision to hold the conference as a virtual meeting. The conference was ultimately held online as a 3-day meeting on May 25-27, 2021. It represented the 10th occurrence of the FASEB Science Research Conferences (SRCs) on Steroid Hormones with Daniel E. Frigo (University of Texas MD Anderson Cancer Center, Houston, TX, USA), Zeynep Madak-Erdogan (University of Illinois Urbana-Champaign, Urbana, IL, USA), and Franck Mauvais-Jarvis (Tulane University, New Orleans, LA, USA) as chairs, and the 12th International Meeting on Rapid Responses to Steroid Hormones (RRSH 2020) with Matthias Barton (University of Zurich, Zurich, Switzerland) and Eric R. Prossnitz (University of New Mexico, Albuquerque, NM, USA) as chairs. The FASEB and RRSH conferences are usually well received by the scientific community since many presentations and discussion topics include unpublished, cutting-edge research. The combined conference brought together scientists and clinicians from all areas of biology and medicine, covering a broad range of topics related to steroid hormone and steroid hormone receptor function in physiology and human health. The program included one keynote speaker, 38 scheduled invited speakers, 18 short talks ("lightning presentations") and 28 virtual poster presentations. The conference drew a record attendance of 110 participants, reflecting an increasing interest in steroid hormone signaling in the scientific community. In terms of diversity, women constituted over 55% of attendees and over 40% of all invited speakers. Early career scientists (defined as faculty with <10 years of experience, postdoctoral associates, and graduate students) were also well represented, comprising 55% of all conference attendees. The welcome address was given by Daniel E. Frigo on behalf of FASEB, and Eric R. Prossnitz on behalf of RRSH, who, together with other organizers, led the program. Keynote speaker Donald McDonnell (Duke University School of Medicine, Durham, NC, USA) set the stage of the conference with his intriguing lecture, "If we knew then what we know now, what would we have done differently to exploit nuclear receptors as drug targets?" Dr McDonnell, who discovered several mechanisms that led to drug treatments for hormone-responsive cancers, provided the audience with a lifetime view of his work, also looking back at the beginnings of field, which he and others pioneered. His lecture was followed by the first session of the day on nuclear steroid receptor regulation of metabolism, led by Sayeepriyadarshini Anakk (University of Illinois Urbana-Champaign). A series of lectures by Adriana Maggi (University of Milan, Italy), Carolyn Cummins (University of Toronto, Toronto, ON, Canada), Andrea Hevener (University of California, Los Angeles, CA, USA), Sheng Wu (Johns Hopkins University, Baltimore, MD, USA), Brian Feldman (University of California, San Francisco, CA, USA), Wen Xie (University of Pittsburgh, Pittsburgh, PA, USA), and Warren Thomas (Royal College of Surgeons in Ireland, Dublin, Ireland) presented updates on metabolic functions of estrogen, androgen, and glucocorticoid receptors, as well as evidence for functional roles for estrogen sulfotransferase and steroid sulfatase in energy metabolism, and how aldosterone regulates renal Na+ reabsorption through novel protein kinase D isoforms. The lectures were followed by lively discussions moderated by the session chairs, even though the meeting was held online. Following the first session, Dr Yvette Seger, FASEB Director of Science Policy, introduced the science policy of FASEB and moderated a round table discussion on the subject. The second half of the first day of the conference was dedicated to clinical aspects of therapies targeting steroid hormone receptors. The session was chaired by Jay Gertz (University of Utah, Salt Lake City, UT, USA) and Martin Wehling (University of Heidelberg, Heidelberg, Germany). Lectures addressed many areas of clinical medicine and disease, including mineralocorticoid receptor function in the treatment of cardiovascular disorders, thyroid receptor signaling in cancer, and membrane progesterone receptor function in the uterus, as well as epigenetics and cistromics in cancer and clinical trials. Lectures were presented by Iris Jaffee (Tufts University, Boston, MA, USA), James Pru (University of Wyoming, Laramie, WY, USA), Paul Davis (Albany Medical College, Albany, NY, USA), Wilbert Zwart (Netherlands Cancer Institute. Amsterdam, The Netherlands), and Mathieu Lupien (University of Toronto). Following the clinical session, a number of young investigators (Florian Le Billan, University of Toronto; Alicia Arredondo Eve, University of Illinois Urbana-Champaign; Ximena Calle Chalco, University of Chile, Santiago, Chile; Innocence Harvey, Pennington Biomedical Research Center, Baton Rouge, LA, USA; and Jia Xu Li, University of Toronto), presented 3-minute poster abstract summaries, which were part of the subsequent virtual poster session presented the same afternoon and well received by the online audience. The second day of the conference began with the morning session focusing on systems biology approaches to interrogate nuclear steroid receptor functions that was chaired by Andrea Cignarella (University of Padova, Padua, Italy) and Lindsey Trevino (City of Hope, Duarte, CA, USA). Topics presented in this session included glucocorticoid receptor-dependent transcription in single cells and individual genes (Trevor Archer, National Institute of Environmental Health Sciences, Durham, NC, USA), imaging of nuclear receptor actions at the single cell level (Fabio Stossi, Baylor College of Medicine, Houston, TX, USA), subcellular localization of estrogen receptor (ER) and cardiometabolism (Pierre Gourdy, University of Toulouse, France), mechanisms of ER enhancer function (Lee Kraus, University of Texas Southwestern Medical Center, Dallas, TX, USA), and steroid G protein–coupled receptor (GPCR)-mediated renal fibrosis in Drosophila (Marc Tatar, Brown University, Providence, RI, USA). Lectures were again followed by talks given by young investigators (Eriko Katsuta, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; Ayca Mogol, University of Illinois Urbana-Champaign; Qianying Zuo, University of Illinois Urbana-Champaign; and Kendall Langsten, Wake Forest School of Medicine, Winston-Salem, NC, USA) and by a career development workshop, "Presenting your science to the public," by Mila Becker, Chief Policy Officer of the Endocrine Society. The afternoon session was chaired by Martin Kelly (Oregon Health and Science University, Portland, OR, USA) and included a number of presentations on different aspects of steroid functions in the brain. Gabriele Rune (University of Hamburg, Germany) presented insights into the sex-dependent effects of neurosteroids in the hippocampus; Charlotte Cornil (University of Liège, Belgium) discussed nuclear and membrane actions of neuroestrogens in the control of male sexual behavior, and Margaret Mohr (University of California, Los Angeles) provided an update on estradiol-induced hypothalamic progesterone synthesis during pubertal development. In the second half of the session, Kevin Sinchak (California State University, Long Beach, CA, USA) discussed how neuroprogesterone and progesterone receptor regulate the luteinizing hormone surge, John Meitzen (North Carolina State University, Raleigh, NC, USA) gave a talk on how estradiol rapidly modulates excitatory synapse properties in the nucleus accumbens, and Karyn Frick (University of Wisconsin, Madison, WI, USA) discussed ERβ activation as a potential treatment for alleviating menopausal symptoms, such as hot flashes. The second day ended with a third lightning round, with four short talks given by young investigators (Michael Saikali, University of Toronto; Dominik Awad, University of Texas MD Anderson Cancer Center; Ashlie Santaliz Casiano, University of Illinois Urbana-Champaign; and Cameron Leyers, Medical University of South Carolina, Charleston, NC, USA), summarizing their poster presentations. The last day of the conference was dedicated to novel roles of steroids and steroid receptors in neoplastic and other diseases. The morning session, "Novel functions of steroid receptors in cancer," was chaired and moderated by Christy Hagan (University of Kansas, Lawrence, KS, USA) and Stephen Hammes (University of Rochester, Rochester, NY, USA). The session was opened by Rosamaria Lappano (University of Calabria, Rende, Italy), who spoke about the role of the membrane estrogen receptor G protein–coupled estrogen receptor (GPER) in breast cancer, followed by Carol Lange (University of Minnesota, Minneapolis, MN, USA), who discussed the signaling properties of progesterone receptor and glucocorticoid receptors in stemness, and Marina Holz (New York Medical College, Valhalla, NY, USA), who presented new data on estrogen/mTOR cross talk in lymphangioleiomyomatosis and breast cancer. These lectures were followed by Matt Sikora (University of Colorado, Anschutz, CO, USA) who shared recent progress on the role of ERs in the therapy response and resistance in lobular carcinoma breast cancer and by Scott Tomlins (Strata Oncology, Ann Arbor, MI, USA), who gave a talk on high-throughput -omics to identify driver mutations and gene fusions in cancer. The session also featured short talks from five young investigators, with data from their virtual posters (Anasuya Das Gupta, University of Illinois Urbana-Champaign; Sarah El Kharraz, KU Leuven, Belgium; Asmaa El-Kenawi, Moffitt Cancer Center, Tampa, FL, USA; Wanting Han, University of Massachusetts Boston, Boston, MA, USA; and Thu Trung, University of Minnesota). In the first afternoon session of day 3 of the conference, Donald DeFranco (University of Pittsburgh) and Ellis Levin (University of California, Irvine, CA, USA) moderated a series of lectures on new mechanisms and approaches of how to target steroid receptors. Elahe Mostaghel (Fred Hutchinson Cancer Center, Seattle, WA, USA) centered his discussion on prostate cancer and how adrenal androgens and androgen receptor (AR) axis inhibition may contribute to therapy resistance and serve as predictors of the therapeutic response. Douglas Kojetin (Scripps Research Florida, Jupiter, FL, USA) then presented evidence on how to use nuclear magnetic resonance spectroscopy to visualize ligand-induced peroxisome proliferator-activated receptor γ (PPARγ) repression. Edward Filardo (University of Iowa, Iowa City, IA, USA) discussed dual specificity proteolysis-targeting chimeras (PROTACs) targeting GPER and ERs, and John Katzenellenbogen (University of Illinois Urbana-Champaign) presented recent evidence from his laboratory demonstrating ERβ effects in response to very low-affinity ER ligands. All talks were followed by questions from the online audience, with lively and engaging discussions moderated by the chairs. The subsequent afternoon session, which concluded the conference, was chaired by Kristy Brown (Weill Cornell Medicine, New York, NY, USA) and Subhamoy Dasgupta (Roswell Park Comprehensive Cancer Center). The session focused on mechanisms of cross talk between nuclear steroid receptors and metabolic pathways. Ian Mills (Queens University Belfast, Belfast, UK) discussed how androgens regulate metabolism in prostate cancer, and Rebecca Riggins (Georgetown University, Washington, DC, USA) presented evidence for novel functions of ER-related receptor β (ERRβ) in the pathogenesis of glioblastoma. Giorgia Zadra (National Research Council of Italy, Rome, Italy) reported data on the modulation of intra-tumor lipid metabolism via AR. Erik Nelson (University of Illinois Urbana-Champaign) then discussed how cholesterol, ER, and liver X receptors (LXRs) modulate the tumor microenvironment in breast cancer, and Philip Shaul (University of Texas Southwestern Medical Center) closed the meeting presentations with data from his and other laboratories on endothelial ER signaling and its effects on cardiometabolic health and disease. Despite the challenges imposed by COVID-19 and the virtual character of the conference, all sessions saw lively discussions and participation from the online audience. Results from the feedback evaluation were very positive regarding the organization of the meeting and the selection of topics. More than 90% of attendees who provided feedback gave favorable comments regarding the general sessions, poster sessions, and the scientific content of the conference. However, there were a few who noted issues with how quickly attendees could access desired on-demand content. Regardless, essentially all respondents of the feedback evaluation indicated that they plan to attend the next meeting, which will be held in 2 years' time, and that they recommend attending this meeting to other researchers in the field. Many of the speakers and presenters have agreed to write a contribution on the topic of their talks for the conference proceedings, which, as for the last 20 years,9-15, 18-27 will be published in the journal Steroids as a Virtual Special Issue in 2022. The organizers express their gratitude to FASEB and to the numerous sponsors of the meeting, which are listed in the Acknowledgments, especially the US National Institutes of Health (NIH) for providing funding to sponsor virtual travel awards. These awards helped to recognize the contributions of students and postdoctoral trainees in the difficult times of the COVID-19 pandemic, leading to increased attendance at the meeting by junior researchers. Indeed, with the support of the NIH/National Institute of Diabetes and Digestive Diseases and the National Cancer Institute (NCI), virtual travel awards were awarded to every student or postdoc who expressed interest in attending the online conference. The next conference (in the form of the 13th International Meeting on Rapid Responses to Steroid Hormones, RRSH 2022) will be held in September 2022 in Paris, France, at the historic venue of the Sorbonne Université, which reaches back to the year 1257 and is one of the oldest and most prestigious universities in the world.28 The organizers are planning for the first in-person meeting after four years and hope to welcome scientists active in all fields of steroid hormone research and medicine in Paris next year. The authors extend special thanks to FASEB for their assistance throughout the organization of this conference, especially Andrea Bauerfeind for her support with organizing the online conference. The authors also thank Silvy Song, their FASEB conference manager, for her hard work in ensuring a well-organized and smoothly run meeting, as well as Bahara Saleh, who was instrumental in coordinating the meeting's sponsors and finances. They also thank Paul Mermelstein, who helped plan initial stages of the meeting. Finally, they thank their sponsors for their maintained support throughout the COVID-19 pandemic, as well as the US National Institutes of Health (NIH)/National Institute of Diabetes and Digestive Diseases (NIDDK) and National Cancer Institute (NCI) for providing generous support for the conference (R13 DK126171). This conference was supported by generous contributions from FASEB, Dr Paul J. Davis (Pharmaceutical Research Institute at Albany College of Pharmacy and Health Sciences, Albany, NY, USA), the University of Illinois Urbana-Champaign (Urbana, IL, USA), the University of New Mexico (Albuquerque. NM, USA), Tulane University (New Orleans, LA, USA), AbbVie (Lake Bluff, IL, USA), Pfizer (New York, NY, USA), and the journals Science Signaling (American Association for the Advancement of Science, Washington, DC, USA), the Journal of Biological Chemistry (American Society for Biochemistry and Molecular Biology, Rockville, MD, USA), Steroids (Elsevier, Amsterdam, The Netherlands), the Journal of Neuroendocrinology (John Wiley & Sons, Hoboken, NJ, USA), and Endocrine-Related Cancer (Society for Endocrinology, North Bristol, UK). This conference was supported by grant R13 DK126171 from NIH/NIDDK and NCI. M. Barton is supported by the Swiss National Science Foundation (grants 108 258 and 122 504); D. E. Frigo is funded by NIH (grants R01CA184208 and P50CA140388); Z. Madak-Erdogan is funded by the US Department of Agriculture/National Institute of Food and Agriculture (grants ILLU-698-331 and ILLU-698-924); F. Mauvais-Jarvis is funded by NIH (grants DK107444 and DK074970) and a US Department of Veterans Affairs Merit Award (BX003725); and E. R. Prossnitz is supported by NIH (grants R01 CA163890, R01 CA194496, P30 CA118100, P20 GM121176) and Dialysis Clinic, Inc (Nashville, TN, USA; grant RF#C3937). The views expressed in written conference materials or publications and by organizers, speakers, and moderators do not necessarily reflect the official policies of the NIH, nor does mention by trade names, commercial practices, or organizations imply endorsement by the US Government. M. Barton conceived and wrote the manuscript; D. E. Frigo, Z. Madak-Erdogan, F. Mauvais-Jarvis, and E. R. Prossnitz contributed and/or edited content.