Abstract IA034: Compromised myoepithelial cell differentiation correlates with DCIS to IDC transition

DCIS, breast cancer confined to mammary ducts, shares genomic and transcriptomic signatures with IDC. However for DCIS patients, standard of care for localized breast cancer remains controversial, as treatment reduces local recurrence but does not reduce risk of distant recurrence or mortality. Further, as the risk of dying from DCIS is ~5-20 fold less than from early stage breast cancer, questions remain concerning treatment harms. The fact that treatment does not reduce DCIS death rates provides indirect evidence that DCIS-stage tumor cells can disseminate and serve as reservoirs for metastatic disease. Since presence of myoepithelium is the clinical determinate of non-invasive disease, death from DCIS also implies that myoepithelial cell loss is not required for tumor cell dissemination. Here, we investigate whether changes in myoepithelial cell differentiation, rather than overt cell loss, associate with DCIS tumor cell dissemination. Using murine DCIS models and human DCIS tissue, our group reported sequential loss of myoepithelial cell differentiation markers p63, calponin, and SMA prior to progression to IDC. In human DCIS lesions delineated into low and high risk (pure DCIS vs mixed DCIS with IDC), loss of myoepithelial p63, calponin and SMA occurred more frequently in high risk DCIS lesions. Mice transgenic for calponin knockdown in the myoepithelium were at increased risk for mammary cancer. Combined, these data implicate loss in myoepithelial cell differentiation as a mediator of DCIS progression and dissemination. In human DCIS, compromised myoepithelium correlates with microinvasion and an immune infiltrate enriched in PD1+CD8 T cells. To address the role of immune cells in myoepithelial cell barrier function, we investigated 6 different immune competent mouse models of intraductal cancer (DCIS). While loss of myoepithelial differentiation markers were evident, IDC lesions developed in the absence of DCIS. Similarly, in immune compromised hosts, only IDC lesions were detected after intraductal injection of murine tumor cells, whereas human tumor cells formed stable DCIS lesions. In vitro, murine mammary tumor cells were more motile than human lines, and when tumor cells were co-cultured with myoepithelial cells, fewer myoepithelial to myoepithelial cell contacts were observed in the presence of the mouse tumor cells. Finally, in women, we find the differentiation state of mammary myoepithelium to be modulated by reproductive state, with myoepi