Abstract P4-04-07: Progesterone promotes immunomodulation and tumor development in the murine mammary gland
Authors: Werner Lauryn R , Gibson Katelin A , Goodman Merit L , Helm Dominika E , Walter Katherine R , Holloran Sean M , Trinca Gloria M , Hastings Richard C , Yang Howard H , Hu Ying , Wei Junping , Lei Gangjun , Yang Xiao-Yi , Madan Rashna , Molinolo Alfred A , Markiewicz Mary A , Chalise Prabhakar , Axelrod Margaret L , Balko Justin M , Hunter Kent W , Hartman Zachary C , Lange Carol A , Hagan Christy R 
Published: March 2022

Abstract
Clinical studies have linked usage of progestins (synthetic progesterone) to breast cancer risk. However, little is understood regarding the role of native progesterone (P4), signaling through the progesterone receptor (PR), in breast tumor formation. Recently, we reported a link between PR and immune signaling pathways, showing that P4/PR can repress type I interferon signaling pathways. Given these findings, we sought to investigate whether P4/PR drive immunomodulation in the mammary gland and promote tumor formation. To determine the effect of P4 on immune cell populations in the murine mammary gland, mice were treated with P4 or placebo pellets for 21 days. We found that mice treated with P4 exhibited changes in the mammary gland indicative of an inhibited immune response compared to placebo-treated mice. To assess the effect of PR overexpression on mammary gland tumor development as well as immune cell populations in the mammary gland, a transgenic mouse model was used in which PR is overexpressed throughout the entire mouse. Immune cell populations were assessed in the mammary glands by flow cytometry, which revealed decreased numbers of various immune cell populations. Transgenic mice were also monitored for mammary gland tumor development over a 2-year timespan. Following development of mammary gland tumors, immune cell populations in the tumors and spleens of transgenic and control mice were analyzed by flow cytometry. Upon long-term monitoring, we determined that multi-parous PR overexpressing mice developed significantly more mammary gland tumors than control mice. Additionally, tumors from PR overexpressing mice contained fewer infiltrating immune cells, and RNA sequencing analysis of tumor samples revealed that immune-related gene signatures were lower in tumors from PR overexpressing mice as compared to control mice. Finally, we utilized syngeneic mammary gland tumor models to evaluate the effect of P4 on the growth of PR+ mammary gland tumors in vivo, which revealed that P4 promoted tumor growth and decreased immune cell infiltration of PR+ mammary gland tumors. Together, these findings offer a novel mechanism of P4-driven mammary gland tumor development and provide rationale in investigating the usage of anti-progestin therapies to promote immune-mediated elimination of mammary gland tumors.
Citation Format: Lauryn R Werner, Katelin A Gibson, Merit L Goodman, Dominika E Helm, Katherine R Walter, Sean M Holloran, Gloria M Trinca, Richard C Hastings, Howard H Yang, Ying Hu, Junping Wei, Gangjun Lei, Xiao-Yi Yang, Rashna Madan, Alfred A Molinolo, Mary A Markiewicz, Prabhakar Chalise, Margaret L Axelrod, Justin M Balko, Kent W Hunter, Zachary C Hartman, Carol A Lange, Christy R Hagan. Progesterone promotes immunomodulation and tumor development in the murine mammary gland [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-07.