Abstract 5800: Anti-metastatic potential of pitavastatin in triple-negative breast cancer via targeting breast cancer stem-like properties and STAT3 signaling

Abstract

Abstract Triple-negative breast cancer (TNBC) is the most deadly and aggressive phenotype, with a higher rate of metastatic recurrence. TNBC does yet have a suitable treatment option other than cytotoxic anticancer drugs. Although pitavastatin has been shown to exert anti-proliferative effects and cytotoxicity in various types of cancer cells, the precise mechanisms underlying pitavastatin’s anti-cancer effects in TNBC have not been fully elucidated. We sought to investigate the mechanism of pitavastatin-induced apoptosis and its effects on cancer stem cell (CSC)-like characteristics in TNBC. Exposure to pitavastatin induced mitochondria-mediated apoptotic cell death in BT549 and 4T1 cells. Mitochondrial dysfunction was accompanied with a robust production of reactive oxygen species (ROS) and collapse of mitochondrial membrane potential (MMP), resulting in subsequent activation of caspase-3/-7 and PARP cleavage. Pitavastatin effectively suppressed CSC-like properties in TNBC via targeting CD44+/CD24- and CD49f+/CD24- phenotypes, as well as impediment of mammosphere formation in vitro. This phenomenon was accompanied with dysregulation of STAT3 survival pathway, concomitant with significant downregulation of cyclin D1, survivin and vimentin. Pitavastatin effectively targets both the proliferating TNBC tumor cells and CSCs via the dysregulation of STAT3 and suppression of CSC-like properties, markedly reducing angiogenesis and tumor growth, coinciding with decreased Ki-67 expression. It is noteworthy that pitavastatin considerably suppressed metastasis, coinciding with significant reduction of MMP-2, MMP-9 and VEGF in the circulating blood of mice. Our findings highlight that pitavastatin may be potentially effective for the treatment of metastatic TNBC. Citation Format: Dongmi Ko, Juyeon Seo, Seongjae Kim, Soeun Park, Minsu Park, Kee Dal Nam, Yong koo Kang, Sora Seock, Eunsun Jung, Yoon-Jae Kim, Jaeyoun Park, Ji Young Kim, Jae Hong Seo. Anti-metastatic potential of pitavastatin in triple-negative breast cancer via targeting breast cancer stem-like properties and STAT3 signaling. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5800.