Abstract 5179: Inflammatory breast cancer cell motility: Understanding the role of E-cadherin and gli1 in IBC migration and the development of a novel high content assay to assess cell migration

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Inflammatory Breast Cancer (IBC) is a highly aggressive subtype of breast cancer and is now regarded as clinicopathologically distinct from neglected locally advanced breast cancer (LABC). In addition, African-Americans, native Americans and younger women are disproportionately affected with IBC having the worse survival. The molecular mechanisms underlying the invasiveness of IBC are not clear. Interestingly, upregulation of the integral membrane protein E-cadherin is the marker reported to be seen most consistently in IBC. In contrast to IBC, E-cadherin is typically reduced in most cancers and the subsequent loss in cell-cell adhesion results in the rapid progression to an invasive and metastatic phenotype. Inactivation of the E-cadherin cell adhesion system can occur by a number of genetic and epigenetic mechanisms. Gli1, the main transcriptional activator of hedgehog signaling, can promote loss of E-cadherin. Gli1 induces expression of Snail which is then found to downregulate E-cadherin expression. In an IBC cellular model, SUM149, we have identified elevated levels of Gli1. Further, inhibition of Gli1 using siRNA caused apoptosis in these cells. We hypothesize that the invasiveness of IBC cells is modulated in part by a connection between E-cadherin and Gli1 levels in IBC and that modulating this pathway will lead to changes in IBC cell motility. This project has two main objectives: 1), Investigate the expression levels of E-cadherin and Gli1 in IBC cells and their roles in IBC motility, and 2), Develop and validate a high content microscope-based assay for measuring motility of IBC cells. Cell motility assays were performed in six-well plates with Gli1 siRNA treated SUM149 cells that resulted in reduced motility and viability of these cells compared to control siRNA treated cells. These results suggest that targeting Gli1 can reduce IBC's invasiveness. This pathway provides opportunities for identifying molecules that might affect tumor invasiveness. We have also developed a novel live cell high content phenotypic screen for modulators of IBC cell motility that may potentially lead to new therapeutics for IBC. An understanding of how any of these molecules affect the Gli-Snail-E-cadherin system would provide useful tools for better probing the role of this pathway in IBC. Furthermore, the high content migration phenotypic assay should be generally applicable to investigating a range of invasive cancer types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5179.