97P The Role of Id Proteins in the Induction of Tumor-Initiating Cells During Pulmonary Colonization of Metastatic Breast Cancer

Abstract

ABSTRACT Breast cancer studies have revealed distinct subpopulations of tumor cells with a high capacity for de novo tumor growth initiation. Tumor-initiating cells (TICs) constitute a small percentage of the bulk tumor and may be responsible for breast cancer relapse in patients. Recently, it has been shown that induction of the epithelial-to-mesenchymal transition (EMT) can trigger reprogramming of cells to a TIC-like phenotype, suggesting a direct relationship between EMT and TIC. Our studies demonstrate that the transcriptional regulator Id1, which has been shown to be important in maintaining the self-renewal and stem cell properties in a variety of normal cell lineages, can induce TIC properties in breast cancer cells independently from EMT. Importantly, factors such as Snail, Twist and TGF-b, which induce EMT and TIC potential, also induce Id expression and we show Id is required for the maintenance of TIC properties. In various mouse models of breast cancer, sporadic Id expression is localized to the invasive edge of the primary tumor, while it is more widely expressed in lung metastatic sites. It has been previously shown that the Id proteins Id1 and Id3 are required for the re-initiation of pulmonary metastatic lesions, which fits well with our discovery of the induction of TICs by Id1 over-expression. But in addition to re-initiation, in order to colonize the metastatic site cells also undergo a mesenchymal-to-epithelial transition (MET). Over-expression of Id1 may also fulfill this need as we show that Id1 over-expression is correlated with a more epithelial phenotype. Furthermore, breast cancer cells that have undergone EMT due to Twist over-expression revert to an epithelial phenotype upon Id1 over-expression while maintaining their TIC properties. As a possible mechanism of Id1 induction, we have observed that TGF-b induces Id1 expression in Snail and Twist over-expressing cells. Therefore we propose that TGF-b up-regulation of Id1 in cells undergoing EMT (i.e. at the primary site) is sufficient to maintain the TIC character of these cells even when factors maintaining an EMT state are no longer present (i.e. during MET at the metastatic site). Disclosure All authors have declared no conflicts of interest.