AURKA/KAP1 signaling in breast cancer metastasis

About This Grant

PROJECT SUMMARY/ABSTRACT Metastatic Breast Cancer (MBC) is an incurable disease, especially critical in a triple-negative (ER-/PR-/HER2) subtype of breast cancer (TNBC) due to its early emergence of metastases and lack of targeted therapy. Remarkable progress in diagnosing and treating early-stage breast cancer (BC) shows the critical need for early detection of cancers with high risk of dissemination to reduce mortality. Our team recently discovered a new marker of early cancer dissemination and metastasis - nuclear AURKA protein (N-AURKA). The nuclear AURKA expressing TNBC cells are highly invasive and disseminate early from oxygenated tumors via induction of unique gene expression signature enriched in cell migration/invasion (escape) genes and repression of adaptation genes (glycolysis, angiogenesis). We found that differential gene expression depends on the KAP1 - heterochromatin assembly factor. We show that N-AURKA recruits KAP1 to reduce chromatin accessibility. N- AURKA binding to KAP1 promotes its dimerization and sumoylation, which is needed for heterochromatin assembly and transcription repression. This phenomenon and its regulation by N-AURKA is novel and might be key to disseminating early-stage BCs. This application aims to determine KAP1-dependent transcriptome changes in N-AURKA cells leading to early oxygenated cancer dissemination. Our central hypothesis is that N- AURKA activates KAP1-dependent chromatin remodeling repressing adaptation genes that have promoters with KAP1 binding sites, thus inducing oxygenated cancer dissemination. Novel drugs designed by our group degrading N-AURKA will halt dissemination and, thus, metastasis. This hypothesis will be tested by executing the following specific aims: Aim 1: Determine the role of KAP1 in N-AURKA-driven transcriptome changes. We hypothesize that N-AURKA affects the expression of HIF1-dependent genes via the recruitment of KAP1. Aim 2: Determine the impact of KAP1 depletion on N-AURKA-driven oxygenated dissemination in TNBC mouse models. Aim 3. Determine the efficacy of PROTAC therapy specifically targeting Nuclear AURKA against early metastasis. The combination of innovative modeling approaches and new therapies will delineate the mechanisms of oxygenated dissemination affecting patients with early-stage and residual disease. Mechanistic understanding of how N-AURKA/KAP1 axis controls oxygenated cancer spread will majorly impact early metastatic cancer diagnostics and treatment.