Abstract 588: Lrig1 suppresses breast cancer stem cell expansion and promotes mesenchymal to epithelial transition

Abstract

Abstract Leucine-rich repeats and immunoglobulin-like domains-1 (Lrig1) is known as a negative regulator of oncogenic receptor tyrosine kinases (ErbB, Met and Ret); and low Lrig1 expression correlates with poor patient prognosis in breast cancer. Lrig1 has been found to maintain stem cell quiescence and marks a subset of quiescent intestinal stem cells where its loss leads to heightened ErbB expression and duodenal adenomas. Lrig1 is defined as a tumor suppressor in healthy tissue such as intestine and epidermis where Lrig1 loss leads to stem cell expansion and epidermal hyperplasia. However, the role of Lrig1 in cancer stem cells (CSCs) and as a metastatic suppressor is unknown. Lrig1 expression is lowest in the highly invasive breast cancer subtype MDA-MB-231, and Lrig1 expression is highest in the weakly invasive luminal A breast cancer subtype. In patients, high Lrig1 expression exhibits longer relapse-metastatic free survival suggesting that Lrig1 expression protects against metastatic relapse. We hypothesized that Lrig1 suppresses breast CSC expansion and promotes mesenchymal to epithelial transition. Our results indicated that restoration of Lrig1 in highly aggressive cell lines promoted mesenchymal to epithelial transition (MET) and a loss of invasive morphology in 3D matrigel cell culture. These results demonstrated that Lrig1 suppressed cell proliferation in both 2D and 3D matrigel cultures and suppressed tumorsphere formation 10-fold. Importantly, we have shown that Lrig1 is down-regulated in the hTERT-immortalized mammary epithelial cell line-twist ER, (HMLE-twist ER) which undergoes EMT. When Lrig1 is knocked-down in HMLE-twist ER by shRNA, the results showed that loss of Lrig1 enhanced mesenchymal and stem cell expansion. These observations suggest that Lrig1 may play a role in EMT transition in metastasis, as well as providing a whole new area of therapeutic targets in breast cancer along with an improved basic understanding in cancer stem cell biology. Note: This abstract was not presented at the meeting. Citation Format: Nucharee Yokdang, Colleen Sweeney. Lrig1 suppresses breast cancer stem cell expansion and promotes mesenchymal to epithelial transition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 588. doi:10.1158/1538-7445.AM2014-588