Commentary: Introduction to The Year in Basic Science Series

Abstract

This year, in response to member input and suggestions to highlight the vibrant basic science of endocrinology, The Endocrine Society Annual Meeting (ENDO 08) introduced a new feature, The Year in Basic Science series. Among the many interests and strengths of our members, three broad areas were chosen for initial consideration: nuclear receptors, kinase signaling, and hormones and cancer. Speakers were invited to present and discuss important publications during the past year between annual meetings (roughly June to June), and to put these findings into broad perspective for the endocrine community. Three distinguished researchers, Bert O'Malley, Tony Means, and Kate Horwitz, graciously agreed to participate in the inaugural venture, and this series of articles is based on their presentations at ENDO 08. Each individual approached this somewhat daunting task slightly differently. However, all three observed important and often common themes that ultimately link current basic molecular findings to broad translational and clinical problems, including metabolism and energy balance, neuronal migration and synapse formation, long-term memory formation, and endocrine pathology in cancer, reproduction and osteoporosis.

“THE YEAR IN Basic Science: Nuclear Receptors and Coregulators” by Bert O'Malley (1) highlights 10 manuscripts that were chosen based on the author’s poll of 20 scientists, using a point system. The chosen studies used a variety of sophisticated approaches, including crystallization of full-length nuclear receptor pair, chromatin immunoprecipitation of genes and entire chromosomes to identify receptor binding sites and epigenetic signatures defining these sites, and tissues-specific knockouts of receptor or coregulator molecules to dissect endocrine regulatory processes. Several studies emphasize the central importance of coregulators, not just in transcription to define regulatory pathways or as ubiquitin-modified molecular clocks to link protein turnover to transcription, but also on the pathological potency of coregulators that play roles in diseases of metabolism and cancer.

“The Year in Basic Science: Calmodulin Kinase Cascades” by Means (2) concentrated on the calmodulin-CaMK family, and also used a polling approach of colleagues to identify the top eight recent publications in this field. The author organizes the papers around the role of calmodulin kinase kinase b (CaMKKb) as a scaffold protein that organizes molecules in the cascades, and phosphorylating enzymes in two pathways: calmodulin-dependent kinases (CaMK) I and IV, or AMP-dependent kinase (AMPK). Throughout the studies, a variety of cell- and tissue-specific gene knockouts, and several specific inhibitors for CaMK I, II, and IV (KN-93), CaMKK a and b (STO-609) and AMPK (compound C) were used to dissect the roles of individual arms of the signaling cascades. Pathways involving CaMKKb and CaMKI or IV include those for cell survival, neuronal migration, and synaptogenesis. CaMKKb and AMPK-regulated pathways include cellular autophagy, CO₂-induced alveolar epithelial dysfunction, and metabolic pathways such as fatty acid oxidation and energy balance/food intake via regulated hypothalamic expression of neuropeptide Y/agouti protein.

“The Year in Basic Science: Hormones and Cancer Lecture” by Horwitz (3) has a somewhat different approach, in that it concentrates on one specific topic—increased risk of breast cancer associated with hormone replacement therapy (HRT)—prompted by a number of papers discussing recent and current clinical trials, and puts this in context of recent basic science papers. In particular, the combination of progesterone plus estrogen vs. estrogen alone is discussed within the concept of breast cancer stem cells, and how they might be “reactivated” by progesterone. The author hypothesizes that the relatively greater risk for breast cancer in patients taking estrogen plus progesterone HRT may be due to expanding the population of silent, dormant ER+/PR+ breast cancer stem cells by the progesterone component of the therapy.

We thank the authors for their responses to invitations for the meeting and the journal, and hope these perspectives bring the current state of these research areas into focus for our readers, and spark new ideas for future research.