Abstract P56: Suppression of Breast Cancer Growth via Inhibition of c-Myc Expression by RUNX3

RUNX3 has been reported to function as both tumor suppressor and oncogene, depending on cancer type and stage. Yet, what regulates its dualistic behavior is unclear. In human breast cancer, RUNX3 expression is frequently silenced by hypermethylation. Previous studies in luminal-type breast cancer have demonstrated that RUNX3 restoration impedes tumor growth by destabilizing the ERα protein. However, despite the therapeutic potential of inducing RUNX3 expression in breast cancer, its comprehensive role, particularly in hormone receptor-negative breast cancers, remains largely unexplored. To further elucidate the role of RUNX3 in breast carcinogenesis, we generated the MMTV-PyMT;Krt8-CreERT2;Rosa26-lsl-RUNX3 mouse model, enabling conditional induction of RUNX3 expression in Krt8+ mammary epithelial cells and tumor cells within the MMTV-PyMT driven breast cancer. Experimental control MMTV-PyMT mice developed approximately eight tumors per mouse, with transcriptomic analyses revealing the Myc pathway as the predominant driver of tumor cell proliferation. Notably, tumor cells in MMTV-PyMT mice lacked Runx3 expression. By contrast, the induction of RUNX3 significantly suppressed tumor growth compared to control mice. Histological and quantitative PCR analyses revealed significantly reduced c-Myc expression in RUNX3-induced tumors. These findings suggest that RUNX3 inhibits tumor growth by suppressing c-Myc expression. Intriguingly, histological analysis identified two distinct clusters of cancer cell populations – proliferating RUNX3+ cells and non-proliferating RUNX3+ cells. Together, these data indicate the potential coexistence of RUNX3's dual functions within the tumor microenvironment as well as the causal link between RUNX3, c-Myc activity and cancer growth. Further investigations, including spatial transcriptome analysis, are essential to understand the molecular mechanisms regulating the functional switch of RUNX3 in breast cancer. This study highlights the therapeutic potential of RUNX3 restoration in breast cancer treatment and informs on its multiple roles in carcinogenesis. Citation Format: Nawaphat Jangphattananont, Junichi Matsuo, Yong Wei Peng, Linda Shyue Huey Chuang and Yoshiaki Ito. Suppression of Breast Cancer Growth via Inhibition of c-Myc Expression by RUNX3 [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr P56.