Abstract 3597: SUV420H2-mediated regulation of collective invasion in triple-negative breast cancer

Abstract

Breast cancer is the second most common cancer in women and metastasis is the leading cause of breast cancer-related mortality. While the factors leading to metastasis remain poorly understood, epigenetic changes in the cancer cell are likely strongly associated with the shift from primary tumor to metastasis. There are several breast cancer subtypes, the most aggressive of which is triple-negative breast cancer which is difficult to treat in part because it is prone to metastasis. In the early stages of metastasis, cells from the primary tumor invade the surrounding tissue before breaking away and seeding metastases. In some cases, tumor cells invade as clusters of cells that migrate as a group and maintain their cell-cell contacts through a process known as collective invasion. These clusters of collectively invading cells have been shown to seed circulating tumor cell clusters that are more efficient at forming metastases than single tumor cells. SUV420H2 is a histone methyltransferase that trimethylates histone H4 lysine 20 (H4K20me3), an epigenetic mark associated with transcriptional repression. Triple-negative breast cancer has lower levels of SUV420H2 and H4K20me3 levels than more luminal subtypes. Our lab and others have found that downregulation or inhibition of SUV420H2 promotes increased plasticity in the epithelial-to-mesenchymal transition, a transcriptional program associated with cancer metastasis. Our objective was to use a three-dimensional tumor spheroid system to determine the role of SUV420H2 and H4K20me3 on breast cancer invasion. We found that in immortalized non-tumorigenic breast cells grown as spheroids in an extracellular matrix, knockdown of SUV420H2 promotes invasion. Treatment of triple-negative breast cancer spheroids with an inhibitor of SUV420H2 (A196) also leads to an increase in invasion, as well as a shift in invasive phenotype from one where cells invade as single cells to a one where cells invade as collective chains emanating from the central spheroid. This suggests that reduced levels of SUV420H2 and the associated changes in histone marks and transcriptional programming in triple-negative breast cancer promote a phenotypic shift from single cell to collective invasion and may be one factor contributing to the increased metastatic potential of this subtype. Future studies will focus on characterizing the effects of SUV420H2 loss on gene and protein expression as well as chromatin in invading cells in tumor spheroids. Citation Format: Emily Campbell Whitt, Laura M. McLane, Paula M. Vertino. SUV420H2-mediated regulation of collective invasion in triple-negative breast cancer. [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 3597.