Activation of ERß hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behavior and poor prognosis. Current therapeutic options available for TNBC patients are primarily chemotherapy. With our evolving understanding of this disease, novel targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, antibody-drug conjugates, and immune-checkpoint inhibitors, have been developed for clinical use. Previous reports have demonstrated the essential role of estrogen receptor ß (ERß) in TNBC, but the detailed molecular mechanisms downstream ERß activation in TNBC are still far from elucidated. In this study, we demonstrated that a specific ERß agonist, LY500307, potently induces R-loop formation and DNA damage in TNBC cells. Subsequent interactome experiments indicated that the residues 151 to 165 of U2 small nuclear RNA auxiliary factor 1 (U2AF1) and the Trp439 and Lys443 of ERß were critical for the binding between U2AF1 and ERß. Combined RNA sequencing and ribosome sequencing analysis demonstrated that U2AF1-regulated downstream RNA splicing of 5-oxoprolinase (OPLAH) could affect its enzymatic activity and is essential for ERß-induced R-loop formation and DNA damage. In clinical samples including 115 patients from The Cancer Genome Atlas (TCGA) and 32 patients from an in-house cohort, we found a close correlation in the expression of ESR2 and U2AF1 in TNBC patients. Collectively, our study has unraveled the molecular mechanisms that explain the therapeutic effects of ERß activation in TNBC, which provides rationale for ERß activation-based single or combined therapy for patients with TNBC.

Research, practice, and data informed investigations of child and youth suicide: A science to service and service to science approach.

BACKGROUND: Suicide rates for children and adolescents have been increasing over the past 2 decades. In April 2023, the National Institute of Mental Health (NIMH) convened a two-day workshop to address child and youth suicide. PURPOSE: The workshop focus was to discuss the state of the science and stimulate a collaborative response between researchers, death investigators, and data collection teams to build a science to service and service to science approach toward understanding - and ultimately preventing - this growing problem of child and youth suicide. HIGHLIGHTS: Topics that meeting participants highlighted as worthy of further consideration for research and practice were: increasing awareness among death investigators, medical examiners, and coroners that child suicide deaths under age 10 years do occur and should be investigated and documented accordingly; emphasizing the value of science based protocols for child and youth death investigations to enhance consistency of approaches; and articulating needs for postvention services to suicide loss survivors. OUTCOMES: The importance of collecting an accurate and complete cause and manner of death (i.e., unintentional, suicide, homicide, undetermined) among all child decedents, and demographic information such as race, ethnicity, and sexual/gender minority status was underscored as critical for enhanced surveillance. For prevention efforts, approaches to assessing and understanding suicidal thoughts and behaviors among diverse groups of children, and the variability in proximal and distal risk factors are needed to inform opportunities for preventive interventions for diverse communities. The need for consistent measures and processes to improve death investigations, fatality review committees, and coordination between data collection systems and agencies was also raised. PRACTICAL APPLICATIONS: Collaborations among researchers, death investigators, and data collection teams can help to fully describe the child and youth suicide crisis and provide actionable information for new research, and prevention and response efforts.