Abstract 1853: Ovarian steroid hormones promote progression of DCIS by increasing cancer stem cell self-renewal through IL-6 signaling

Introduction: The ability of the ovarian steroid hormones estradiol (E) and progesterone (P) to influence cancer stem cell (CSC) self-renewal and progression of human ductal carcinoma in situ (DCIS) is a critical but understudied area or research. The objective of this study is to characterize steroid hormone signaling involved in CSC self-renewal and invasion in ER+PR+ DCIS. We have found that these hormones can increase CSC self-renewal in a subset of DCIS patients, and that this may be facilitated by activation of the IL-6 pathway. Methods: Mammosphere (MS) assays (an in vitro assessment of CSC self-renewal) and the mouse intraductal (MIND) xenograft model were used to characterize hormonal regulation of the CSC population and invasion potential of primary human ER+PR+ DCIS cells. Additionally, ovarectomized mice were used to create MIND xenografts of ER+PR+ DCIS, treated with E+P or vehicle for 8 weeks, and used for RNA sequencing and immunofluorescent staining. Results: Only a subset of cases responded to E+P in vitro by increasing MS efficiency, indicating increased CSC self-renewal. RNA sequencing of MSs identified genes that differed between vehicle and E+P treatment only in DCIS cases that respond to E+P by increasing MS efficiency. Many of these changes were associated with epithelial mesenchymal transition (EMT), including Twist1, Snai1, MMP9. In E+P-treated MIND xenografts, DCIS cases that respond to E+P by increasing MS efficiency also had higher IL-8 and vimentin (markers of EMT) compared to non-responders (P