Abstract IA034: Compromised myoepithelial cell differentiation correlates with DCIS to IDC transition
Authors: Bernhardt Sarah M. , Mitchell Elizabeth , Russell Tanya , Jindal Sonali , Narasimhan Jayasri , Hoffmann Reuben J. , Benson AeSoon , Schedin Pepper 
Published: December 2022

Abstract
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 myoepithelium during weaning–induced gland involution (an established risk window for breast cancer progression) sharing similarities with myoepithelium of high-risk DCIS lesions. In rodents, recently weaned hosts support increased DCIS to IDC transition. In sum, these studies implicate intrinsic and extrinsic regulators of myoepithelial cells, highlight the need for immune competent mouse models of DCIS, and raise the question of whether species mismatch in xenograft models impacts cellular crosstalk between myoepithelial and tumor cells critical to our understanding of the DCIS to IDC transition.
Citation Format: Sarah M. Bernhardt, Elizabeth Mitchell, Tanya Russell, Sonali Jindal, Jayasri Narasimhan, Reuben J. Hoffmann, AeSoon Benson, Pepper Schedin. Compromised myoepithelial cell differentiation correlates with DCIS to IDC transition [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA034.