Abstract 108: Abi1 positively regulates lung metastasis of aggressive breast cancer in PyMT mouse model

Abstract

Breast cancer is the most commonly diagnosed non-cutaneous cancer in American women and is estimated to cause 40,000 deaths this year. Despite standard of care, breast cancer patients often relapse after a few years of treatment thus highlighting the need for new molecular targets for improved management of metastatic disease. Abelson interactor 1 (Abi1) is an adaptor protein 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 analysis 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. Abi1 has been shown to positively regulate breast cancer cell proliferation, motility, division, and invasion in vitro however its exact role in vivo remains unknown. We therefore hypothesize that Abi1 promotes breast tumor progression and metastasis in a mouse breast cancer model. Using the well-characterized Polyoma Middle T (PyMT) breast cancer model, we conditionally deleted Abi1 from the mammary epithelium and determined the effects on tumor growth kinetics and WAVE complex protein levels. Interestingly, our studies show delayed tumor growth only in mice with heterozygous deletion of Abi1 while homozygote KO mice show relatively unchanged tumor growth. Western blot analyses of Abi1 KO breast tumors show concomitant loss of WAVE complex proteins supporting our previous findings that WAVE complex integrity is dependent on Abi1. Our data also show significant upregulation of Abi2 only in homozygous Abi1 KO mice, suggesting a potential compensatory role for Abi2 that may support primary tumor growth in absence of Abi1. Most interestingly, Abi1 null PyMT mice show significantly reduced incidence of lung metastasis, supporting our hypothesis that Abi1 promotes metastasis of breast cancer cells. In summary, Abi1 loss abrogates lung metastasis in PyMT mice however primary tumor growth remains largely unaffected, possibly due to a compensatory mechanism by a related protein, Abi2. This work will establish the biochemical dynamics between members of the Abi protein family and WAVE complex to improve targeted treatments in aggressive human breast cancer. [Supported by NCI grant R01-CA161018 and Carol M. Baldwin Breast Cancer Research Fund of CNY] Citation Format: Angelina Regua, Isabelle Bichindaritz, Tiffany Caza, Julie R. White, Alexander Nappi, Claudia Mondragon, Mira Krendel, Gennady Bratslavsky, Abirami Sivapiragasam, Leszek Kotula. Abi1 positively regulates lung metastasis of aggressive breast cancer in PyMT mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 108.

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“…ABI2 has a paralog, ABI1, which positively regulates lung metastasis of aggressive breast cancer 93 . Regua et al, (2008) suggest that in the absence of ABI1, its paralog could play a compensatory role that may support primary tumor growth.…”