Abstract 3784: miR-489 induces apoptosis and immunogenic cell death through targeting FOXM1 in triple negative breast cancer cells

Abstract It has been well established that microRNAs (miRNAs) have an important role in cancer sustenance and progression. Our previous studies have established the role of miR-489 as a tumor suppressor miRNA in breast cancer. However, the multiple targets of this miRNA have diversified its mechanism from preventing tumor cell proliferation to promoting cell death pathways. In this study we have aimed to establish the role of miR-489 in cell cycle inhibition, leading to Endoplasmic Reticulum stress (ER stress) and ultimately immunogenic cell death (ICD). Firstly, we found that overexpression of miR-489 in triple negative breast cancer (TNBC) cell lines including MDA-MB-231, BT 549, drastically reduced cell proliferation using colony formation assay and real-time cell analysis. Furthermore, studies like GO analysis, sequence analysis and cell cycle analysis demonstrated that miR-489 induces cell cycle arrest and apoptosis in TNBC by directly targeting FOXM1 and regulating other kinases like CDK1. It was also shown for the first time that miR-489 overexpression induces ER stress and the release of damage associated molecular patterns (DAMPs), consistent with hallmarks of ICD like Calreticulin exposure on cellular surface and ATP release, triggering phagocytosis. It was also established that miR-489-induced apoptosis lead to the elevation of cleaved caspase 3, which was responsible for the activation of PANX1 and the consequent release of ATP. In conclusion, we tried to mechanistically understand the role of miR-489 in cell cycle arrest leading to cellular stress. Stress induced apoptosis and consequent ICD was also a possible outcome and it turned out miR-489 overexpression without any other ICD inducer was good enough to trigger the release of DAMPs and elucidate an immunogenic response. Citation Format: Gourab Gupta, Ryan Titus, Yogin Patel, Shakthika Sarvanan, Hexin Chen. miR-489 induces apoptosis and immunogenic cell death through targeting FOXM1 in triple negative breast cancer cells. [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 3784.