Abstract 6283: Tumor repressive effects of estrogen receptor β mRNA-based therapy in aggressive breast cancers

Abstract Inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) are the most aggressive forms of breast cancer due to their high propensity to develop distant metastases and the lack of specific effective targeted therapies. The failure of previous research to produce viable therapeutic targets combined with the absence of estrogen receptor α (ERα) in TNBC and the majority of IBC led us to explore the second ER (ERβ) as a molecule with targeting potential. We previously reported the anti-metastatic effects of ERβ in both TNBC and IBC. Considering the anti-tumor activity together with the decreased expression of ERβ in IBC and TNBC tumors, we employed an mRNA-based approach to induce tumor-specific upregulation of the receptor and restore its anti-metastatic activity. Our findings show that complexes of ERβ mRNA with lipid nanoparticles (LNPs) enable in vitro translation of a functional protein with strong anti-invasive activity. More importantly, direct administration of ERβ mRNA-LNPs in orthotopically grown IBC and TNBC tumors results in high tumor levels of the receptor and an evident inhibition of metastasis demonstrating for the first time the ability of ERβ mRNA to prevent progression of the disease. Our study may have important clinical implications by establishing ERβ mRNA as a novel and specific therapy intervention that either alone or in combination with existing treatments can substantially repress metastasis, eliminate associated mortality and benefit patients with aggressive breast cancer. Citation Format: Kim Cuong Cap, Aireana Phillips, Karem A. Court Pinto, Kristina D. Zambo, Wei Qian, Jianying Zhou, Jenny Chang, Biana Godin, Christoforos Thomas. Tumor repressive effects of estrogen receptor β mRNA-based therapy in aggressive breast cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6283.