Abstract 6093: Investigating the role of stress induced nuclear relocalization of SIPA1 in breast cancer metastasis

Abstract Breast cancer is the most commonly diagnosed cancer among women in the U.S., and metastasis is the leading cause of deaths in breast cancer patients. This disease presents with an 87.2% 5-year (2015-2021) survival rate in regional tumors which drops to 32.6 % in metastasized cancers. The goal of Hunter laboratory is therefore to understand the dynamics of cancer progression by identifying mechanisms of metastasis. In this study, we hypothesize that when breast cancer cells are under stress during metastasis, the relocalization of metastasis susceptibility proteins to the nucleus is essential for metastatic progression. Previous work in the laboratory revealed that metastasis susceptibility genes were present in the nucleolus, a central stress sensor. During stress, cytoplasmic proteins are sequestered in the nucleolus and the size of the nucleolus increases. We showed that SIPA1 (Signal Induced Proliferation-associated 1), one of the first metastasis susceptibility genes identified in the laboratory, relocalizes to the nucleus under stresses mimicking metastasis. SIPA1 is a mitogen-induced GTPase activating protein predominantly known to be present in the perinuclear region. However, SIPA1 can relocalize to the nucleus, a phenotype associated with poor prognosis in breast cancer patients. In current experiments, we observed that SIPA1 relocalizes to the nucleus in response to stress conditions like heat shock, nutrient deprivation, hypoxia and low dose chemotherapy drugs. This stress-induced relocalization is primarily in nuclear speckles, a splicing factor storage site, and partially in the nucleolus. Additionally, SIPA1 also binds to higher order repeats near the centromeric regions of multiple chromosomes. Through spectral karyotyping, we observed that knocking down SIPA1 in breast epithelial cells alters chromosomal stability. Future experiments involve assays to determine the mechanism of nuclear relocalization of SIPA1 under stress and proximity assays to identify the interacting proteins in the proximity of SIPA1. Revealing mechanisms that control the relocation of SIPA1 in the nucleus, will further clarify the pathways responsible for stress response in breast cancer cells during metastasis. Citation Format: Nirupama S. Kotian, Kent W. Hunter. Investigating the role of stress induced nuclear relocalization of SIPA1 in breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6093.