Abstract B255: Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells.

Abstract

Abstract Breast cancer is the leading cause of cancer death in women. Most of the primary breast cancers express estrogen receptor α (ERα) and they show estrogen-dependent proliferation. Since tamoxifen antagonizes estrogen in breast cancers, it is widely used to treat the primary breast cancers. However, tamoxifen also shows a partial agonistic activity in different tissues and cellular context, which sometimes causes a detrimental effect. An alternative strategy to kill the estrogen signaling is to downregulate ERα protein. We have developed a protein knockdown system to induce degradation of target proteins via the ubiquitin-proteasome system (UPS) in cells. The molecules for protein knockdown, which we named SNIPER (Specific and Non-genetic IAP-dependent Protein ERaser), are composed of two different ligands connected by a linker; one is a ligand for cellular inhibitor of apoptosis protein 1 (cIAP1) and the other is a ligand for a target protein. Accordingly, SNIPER is expected to crosslink a ubiquitin ligase cIAP1 and the target protein in the cells, thereby inducing the cIAP1-mediated ubiquitylation and proteasomal degradation of the target protein. By using tamoxifen as a ligand for ERα, we developed novel SNIPER to knockdown ERα protein. SNIPER(ER) induced degradation of ERα and inhibited estrogen-dependent expression of pS2 gene in an estrogen-dependent breast cancer MCF-7 cells. Intriguingly, after the ERα degradation, the SNIPER(ER)-treated MCF-7 cells undergo rapid cell death. Detailed analysis indicated that SNIPER(ER) caused necrotic cell death accompanied by a release of HMGB1, and reactive oxygen species (ROS) mediate the necrotic cell death in the SNIPER(ER)-treated MCF-7 cells. These results indicate that SNIPER(ER) induces ERα degradation, ROS production and necrotic cell death, implying a therapeutic potential of SNIPER(ER) as a lead for the treatment of ERα-positive breast cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B255. Citation Format: Keiichiro Okuhira, Yosuke Demizu, Takayuki Hattori, Nobumichi Ohoka, Norihito Shibata, Tomoko Nishimaki-Mogami, Haruhiro Okuda, Masaaki Kurihara, Mikihiko Naito. Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B255.