Abstract LB160: The mouse mammary tumor virus mediates the antineoplastic action of decitabine

Abstract

Abstract The purpose of this study is to clarify the role of the mouse mammary tumor virus (MMTV) in cancer growth and in mediating the antineoplastic effect of decitabine, a DNA demethylating agent. In vitro studies have shown that decitabine inhibits cancer cell proliferation by stimulating endogenous retroviruses which in turn activates the production of cytostatic interferon beta (IFN-β). We investigated the potential involvement of endogenous MMTV and the mouse IFN-β in the pharmacodynamics of decitabine using stable knockdown cell lines and MMTV hyper-infection. For the first time, we show that knockdown of MMTV or IFN-β in a mouse mammary cancer cell line (4T1) both rendered the cancer cells more resistant to decitabine in mice bearing 4T1-derived mammary cancer. Mechanistically, decitabine enhanced MMTV expression on the RNA level in both control tumors and tumors with MMTV knockdown, although the degree of enhancement was limited in knockdown tumors. Conversely, infection of a mouse colon cancer cell line (MC38) with MMTV released from 4T1 cells rendered the colon cancer cells more sensitive to decitabine. These data confirm the viral mimicry hypothesis as the mechanism of DNA demethylating agents. Practically, our research suggests the possibility of combining the use of an exogenous virus and a DNA demethylating agent as a new approach to cancer treatment. Citation Format: Sarah Light, Maziar Montazer, Cade Wycoff, Richard Tuttle, Andrew Brola, William Wycoff, Ryan Johnson, Yingguang Liu. The mouse mammary tumor virus mediates the antineoplastic action of decitabine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB160.