Abstract 3643: The role of HBP1 in controlling breast cancer dormancy reawakening

Abstract

Abstract At least 22% of breast cancer (BrCa) cases recur after 3 to 15 years, typically at metastatic sites such as the bone. Bone metastases derive from early disseminated tumor cells that become dormant because of interaction with specific cells that define the endosteal niche (EN) microenvironment. However, outside knowing that dormancy is driven by a p38MAPKhi, ERK1/2lo activation profile, our understanding of what factors regulate dormancy maintenance and reawakening is poor. We used a genomic shRNA screen to identify HBP1 as a suppressor of BrCa dormancy reawakening in a 3D-EN culture system. Our data indicate that under 3D-EN conditions, HBP1 is upregulated by p38MAPK, interacts with the metastasis suppressors, BRMS1 and BRMS1L, and with the histone modifiers, SIN3A and HDAC1-3. We hypothesize that HBP1 suppresses p38MAPK-mediated dormancy reawakening by complexing with BRMS1/BRMS1L/SIN3A to alter cell cycle gene expression through histone landscape remodeling. HBP1 suppresses the expression of cell cycle progression genes, such as MYC and CCND1, and concomitantly upregulates cyclin kinase inhibitors, p16 and p21. HBP1 RNA and protein levels are decreased in BrCa metastases relative to primary tumors, and this downregulation correlates with poorer overall survival. We are investigating whether the anti-histiminic drug, cyproheptadine, which upregulates HBP1 expression through the activation of p38MAPK, can suppress dormancy reawakening of BrCa cells in 3D-EN cultures and in in vivo models of bone dormancy using mouse mammary carcinoma D2A1 cell lines with varying abilities to form active or dormant metastatic bone colonization. Data will be shown addressing how cell-cell interactions and secretory factors between BrCa and bone EN cells facilitates dormancy signaling through a p38MAPK/HBP1/BRMS1 axis, and how drugs such as cyproheptadine agonize that pathway in order to prevent the reawakening that drives the growth of BrCa metastases in the bone, thereby increasing overall survival. Citation Format: Irwin H. Gelman, Seamus Degan, Henry G. Withers, Subrahmanya Anirudh Kaligotla Venkata. The role of HBP1 in controlling breast cancer dormancy reawakening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3643.