Abstract 6543: Progesterone signaling alters the metabolic profile and immune cell landscape of mammary gland tumors

Abstract Estrogen and progesterone signaling together drive hormone-receptor positive breast cancer growth and progression. However, there have been limited studies on the independent role that progesterone and its receptor, the progesterone receptor (PR), play in the development of breast cancer. Using the SSM2 tumor cell line, that expresses both the estrogen receptor (ER) and PR, we treated cells with either progesterone or vehicle (EtOH) and performed RNA-seq. The results of these experiments showed that progesterone treatment changes the metabolism of SSM2 tumor cells in vitro, altering the amount of free cholesterol and fatty acids in conditioned media. Previous studies in the Hagan lab have shown that progesterone signaling promotes mammary tumor growth and changes the immune landscape of the mammary gland towards immunosuppression. Therefore, we performed a tumor study using orthotopic injection of SSM2 tumor cells. Mice were treated with progesterone or placebo at the time of SSM2 tumor cell implantation. The results of this study showed that progesterone increases SSM2 tumor growth. Additionally, to investigate immune cell changes, we performed scRNA-seq on the progesterone and placebo-treated tumors. ScRNA-seq showed that progesterone-treated tumors harbored less CD3+ T cells than placebo-treated tumors. Additionally, progesterone-treated tumors had a greater number of TREM2+ macrophages than the placebo-treated tumors. The findings of our scRNA-seq data corroborated our in vitro findings that progesterone treatment of SSM2 tumor cells changes their metabolic profile. Our findings demonstrate that progesterone signaling promotes an immune suppressed microenvironment in the mammary gland through an increase in TREM2+ macrophages and a decrease in CD3+ T cells. This evidence provides rationale to investigate the use of anti-progestins as a mechanism to overcome the immune-cold tumor microenvironment seen in progesterone receptor positive breast tumors. Citation Format: Eilidh I. Chowanec, Christy R. Hagan, Jason Gertz. Progesterone signaling alters the metabolic profile and immune cell landscape of mammary gland tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6543.