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Estrogen plays multiple roles in health and disease, exerting its effects through the classical estrogen receptors (ERα and ERβ) and the G protein‑coupled estrogen receptor (GPER). Current ER‑targeting ligands, including the therapeutic ERα antagonist tamoxifen, have been shown to cross‑activate GPER. This cross‑activation is hypothesized to contribute to clinically observed endocrine resistance in breast cancer, highlighting the potential benefit of truly ER‑selective antagonists. We report the identification of a novel class of ER‑selective ligands that lack cross‑reactivity towards GPER, identifying a truly ER‑selective agonist (AB‑1) and antagonist (AB‑82P). Importantly, AB‑82P degrades a clinically relevant ERα mutant and exhibits inhibitory effects in cellular models of endocrine resistance. This novel class of ER‑selective ligands can aid in improving our understanding of the individual estrogen receptors in estrogen biology and more importantly, provide a structural basis for the development of new, truly ER‑selective antagonists for the treatment of ERα‑positive breast cancers.

The maintenance of the hematopoietic stem and progenitor cell (HSPC) population is critical to sustaining the adult blood and immune system throughout an organism’s lifespan. The bone marrow microenvironment plays a key role in the regulation of HSPC maintenance and functions. Previous work from our lab has identified the tetraspanin CD82 as an important modulator of HSPC interactions with the bone marrow niche. However, the mechanisms as to how CD82 contributes to the maintenance, trafficking and retention of HSPCs with the niche remained unclear. First, we investigated how CD82 promotes HSPC quiescence, homing and engraftment using a global CD82 knock out (CD82KO) mouse model. Our data demonstrate that CD82 promotes the maintenance of the long-term HSC population within the bone marrow through increased quiescence. Additionally, we demonstrate that CD82KO HSPCs display reduced bone marrow homing and engraftment, identifying a key role for CD82 in these processes. We demonstrate that Rac1 is hyperactivated in the CD82KO HSPCs and inhibition directed to Rac1 restored HSPC homing and migration. We also identified CD82 as a novel regulator of HSPC mobilization. Our data demonstrate that CD82 promotes bone marrow retention, finding increased blood mobilization in the CD82KO mice. Further studies identified the S1PR1 as a key component of CD82-mediated mobilization. Taken together, these data provide evidence that CD82 is a critical regulator of HSPC quiescence, homing, engraftment and mobilization. More importantly, these studies identify CD82 as a potential novel molecular target to enhance HSPC transplantation therapies for treatment of hematological and non-hematological disorders.

The maintenance of the hematopoietic stem and progenitor cell (HSPC) population is critical to sustaining the adult blood and immune system throughout an organism’s lifespan. The bone marrow microenvironment plays a key role in the regulation of HSPC maintenance and functions. Previous work from our lab has identified the tetraspanin CD82 as an important modulator of HSPC interactions with the bone marrow niche. However, the mechanisms as to how CD82 contributes to the maintenance, trafficking and retention of HSPCs with the niche remained unclear. First, we investigated how CD82 promotes HSPC quiescence, homing and engraftment using a global CD82 knock out (CD82KO) mouse model. Our data demonstrate that CD82 promotes the maintenance of the long-term HSC population within the bone marrow through increased quiescence. Additionally, we demonstrate that CD82KO HSPCs display reduced bone marrow homing and engraftment, identifying a key role for CD82 in these processes. We demonstrate that Rac1 is hyperactivated in the CD82KO HSPCs and inhibition directed to Rac1 restored HSPC homing and migration. We also identified CD82 as a novel regulator of HSPC mobilization. Our data demonstrate that CD82 promotes bone marrow retention, finding increased blood mobilization in the CD82KO mice. Further studies identified the S1PR1 as a key component of CD82-mediated mobilization. Taken together, these data provide evidence that CD82 is a critical regulator of HSPC quiescence, homing, engraftment and mobilization. More importantly, these studies identify CD82 as a potential novel molecular target to enhance HSPC transplantation therapies for treatment of hematological and non-hematological disorders.