Abstract 1193: LSR transcript variant iota drives nuclear localization and altered transcriptome regulation in breast cancer

Abstract

Abstract Breast cancer remains the second highest cause of cancer-related deaths among women despite continuous improvements in diagnosis and treatments. African-American (AA) women have higher mortality rates and shorter survival times then Caucasians. Higher prevalence of aggressive triple-negative tumors in young AA women, and increased mortality rates in AA women, at all ages, diagnosed with less aggressive Luminal A tumors denotes cancer disparities in multiple molecular phenotypes. Lipolysis stimulated lipoprotein receptor (LSR) was originally identified as a hepatocyte receptor involved in the dynamics of lipid distribution between the liver and peripheral tissue. Upon activation LSR mediates the binding, cellular uptake, and degradation of triacylglyceride-rich lipoproteins. LSR has also been highlighted as an important regulator of tricellular tight junctions (tTJs). tTJs are specialized junctions within tricellular contacts of epithelial sheets. LSR regulates tTJs through the recruitment and arrangement of several proteins including tricellulin, ILDR1 and ILDR2. While previous studies have described tTJ and hepatic functions of LSR, our lab was the first to directly show LSR enhances aggressive breast cancer cell behaviors including proliferation and migration, and promotes cancer-stem cell properties such as survival in anchorage-independent conditions. Herein, we have taken a closer examination of breast cancer samples, and found nuclear localization of LSR, a novel observation for a proposed membrane localized protein. Moreover, we show nuclear localization is significantly correlated with poor patient outcome. In vitro assays confirmed LSR localizes to the plasma membrane, cytoplasm, and the nucleus. From these results it is clear that LSR has an additional nuclear function that may alter gene expression and promote more severe cancer phenotypes. Of note, given the high breast cancer mortality rate in African-American women, we have looked for and identified LSR SNPs unique to African-Americans. Furthermore, we used in silico sequence analysis and determined putative functional motifs and post-translational modifications of the LSR protein as well as identified nine unique transcript variants of LSR. We then focused upon one variant (Iota), which lacks a transmembrane domain and features a nuclear localization sequence. We used in vitro assays to show cellular localization and behavioral consequence of LSR iota expression in breast cancer cell lines. Collectively, our novel data highlight the complex roles of LSR including alternate transcripts, nuclear localization, and possible enzymatic function, which may impact cancer progression and potentially provide insight into breast cancer health disparities. Citation Format: Katerina D. Fagan-Solis, David A. McDonald, Lynnelle W. Thorpe, Jodie M. Fleming. LSR transcript variant iota drives nuclear localization and altered transcriptome regulation in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1193. doi:10.1158/1538-7445.AM2015-1193