Abstract 3404: Loss of Abi1 abrogates lung metastasis in the PyMT mouse model of breast cancer

Abstract

Abstract This study aims to elucidate the role of Abelson interactor 1 (Abi1), a key protein in the WAVE regulatory complex, in mammary carcinogenesis and metastasis. Breast cancer is the second-leading cause of mortality in women in the United States with an estimated ~200,000 new cases and over 40,000 deaths this year. Despite current treatment modalities, breast cancer patients often relapse after only a few years of treatment thus emphasizing the need for better therapeutic targets. Abi1 is an adaptor protein mainly associated with the WAVE (Wiscott-Aldrich syndrome protein family verprolin homologous) regulatory complex and Arp2/3 (Actin-related proteins 2 and 3)-mediated actin cytoskeleton remodeling. Our bioinformatic and gene expression analyses of human tumor data indicates that Abi1 is frequently upregulated in invasive breast cancers, is associated with poor survival, and may promote an aggressive breast tumor phenotype. Downregulation of Abi1 also abrogates motility and invasion of breast cancer cells, most likely through inactivation of both Src and PI3 kinase as well as certain matrix metalloproteases. We therefore hypothesize that Abi1 positively regulates breast tumor progression and invasion through dysregulation of these cell signaling pathways. To determine the role of Abi1 in breast tumor progression, we used a Cre-lox system to conditionally delete Abi1 in the mammary tissue of Polyoma Middle T (PyMT) breast cancer mice. Abi1 knockout (KO) and control mice were palpated bi-weekly to determine tumor latency and tumors were measured with a caliper to determine total tumor burden. We are currently analyzing changes in tumor kinetics as a result of conditional Abi1 knockout in the mammary epithelium of PyMT mice. Our preliminary studies of indicate slowed tumor growth in Abi1 KO PyMT mice. Western blot analyses of Abi1 KO mammary tumors indicate concomitant loss of WAVE complex proteins supporting our previous findings that WAVE complex integrity is dependent on Abi1. Most interestingly, Abi1 null PyMT mice exhibit significantly reduced incidence of lung metastasis, supporting our hypothesis that Abi1 promotes invasion by breast cancer cells. In summary, Abi1 loss leads to reduction of lung metastasis in PyMT mice, possibly through inactivation of key cell signaling and proliferation pathways such as Src and PI3 kinase. This work will establish Abi1 as a potential prognostic marker and therapeutic target in metastatic breast cancer. Citation Format: Angelina Regua, Isabelle Bichindaritz, Tiffany Caza, Julie White, Robert Adamiecki, Mira Krendel, Gennady Bratslavsky, Leszek Kotula. Loss of Abi1 abrogates lung metastasis in the PyMT mouse model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3404. doi:10.1158/1538-7445.AM2017-3404