Abstract 2284: Progesterone receptor modulates the antigen processing and presentation machinery: Decreasing MHC class I expression on tumor

Abstract Hormone receptor (HR)-positive breast cancers, which account for approximately 75% of all breast cancers and express both estrogen receptor (ER) and progesterone receptor (PR), have been the focus of extensive research. Anti-estrogen and ER-targeted therapies have been highly successful in treating HR+ breast cancer; however, more than one-third of patients eventually develop resistance, underscoring the need for new targeted strategies. Unlike ER, the role of PR in breast cancer progression and immune modulation remains less explored. In previous work, we found that a mouse mammary tumor cell line (E0771) engineered to express mouse progesterone receptor (mPR) and the ovalbumin (OVA) peptide exhibited reduced T-cell-mediated cytotoxicity following progesterone treatment compared with control cells. This progesterone-mediated protection occurred only in mPR+ cells. Flow cytometric analysis further demonstrated decreased MHC class I surface expression in progesterone-treated E0771-Ova-mPR cells relative to vehicle controls. To investigate the underlying mechanisms, we analyzed the expression of genes involved in antigen processing and presentation (APP) of MHC class I molecules. Progesterone treatment reduced RNA levels of Tap1, Tap2, Tapbp, Nlrc5, B2m, and Psmb8, which are essential components of the APP pathway. These findings suggest that progesterone receptor activation suppresses the antigen presentation machinery, leading to reduced MHC class I expression and impaired recognition by cytotoxic T cells. Collectively, our data indicate that progesterone signaling may contribute to immune evasion in HR+ breast cancer through transcriptional regulation of MHC class I APP genes. Citation Format: Julio Tinoco, Eilidh Chowanec, Amanda Glen Heard, Christy R. Hagan. Progesterone receptor modulates the antigen processing and presentation machinery: Decreasing MHC class I expression on tumor abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2284.