Introduction. Due to advances in imaging technology and an increase in mammographic screening, there has been a significant increase in the diagnosis rate of ductal carcinoma in situ (DCIS). At the present time, nearly all women undergo surgical removal of DCIS, often followed by adjuvant radiation and in some cases anti-hormonal therapy. Currently, there are no means by which to diagnose DCIS accurately, or to predict which patients benefit from aggressive therapy. Thus, the recommendation for surgery persists, despite studies which support that not all DCIS will subsequently progress to invasive disease. In this context, animal models can be particularly useful in studying DCIS progression. Here, we present the first in vivo model of DCIS, referred to as Mouse-INtraDuctal (MIND), in which patient-derived DCIS epithelial cells are injected intraductally and allowed to progress naturally in mice. Methods. We performed intraductal injection of DCIS epithelial cells derived from 30 patient samples into 194 total glands. Of the 194, 146 xenografts showed in vivo growth, for a 75% take rate). Among the DCIS samples injected into mice, 18 (103 mouse mammary glands) were followed for a median of 9 months . Among those, 50% (9) showed invasive progression while 50% (9) remained non-invasive. DCIS invasive progression was evaluated by performing immunofluorescene staining using anti-smooth muscle actin (SMA) antibody and confirmed by the loss of SMA around the xenografted DCIS like lesions on 3 consequetive sections of FFPE tissues. Results. Progressed xenografts exhibited invasive progression, evident by the loss of SMA, as early as 6 months following transplantation. Similar to human DCIS, the cancer cells initially formed in situ lesions inside the mouse mammary ducts and mimicked all histologic subtypes including micropapillary, papillary, cribriform, solid and comedo. Among the biomarkers tested, including ER, PR, Ki67, HER2, p53, histology, nuclear and tumor grade, only low ER & PR expression and extent of DCIS growth in xenografts significantly correlated with invasive progression. A high depth targeted sequencing platform (T200) on DNA isolated from LCM captured DCIS of patient and xenograft pairs identified shared (i.e., EGFR) as well as unique (STK11, RUNX1, PIK3CA) mutations in patient/xenograft pairs. Notably, we also observed private mutations that were not shared within the same patient/xenograft pairs. These results indicate the presence of DCIS clonal heterogeneity and that DCIS xenografts may represent one or more clonal subpopulations of patient DCIS. Conclusion. The MIND model represents the first realistic in vivo model that recapitulates human DCIS progression in a manner that represents the inter- and intra-tumoral heterogeneity of human disease. These innovative mouse models will be invaluable for the discovery of molecular signatures of invasive DCIS by allowing comparison of xenografts with variable propensity for invasive progression. These models will enable the discovery of extrinsic factors that regulate DCIS malignancy as well as testing of pharmaceutical and natural compounds for prevention of DCIS progression to invasive disease. Citation Format: Fariba Behbod, Yan Hong, Darlene Limback, Hannan S Elsarraj, Haleigh Harper, Haley Haines, Hayley Hansford, Michael Ricci, Carolyn Kaufman, Mingchu Xu, Jianhua Zhang, Lisa May, Therese Cusick, Marc inciardi, Mark Redick, Jason Gatewood, Alison Aripoli, Ashley Huppe, Onalisa Winblad, Christa Balanoff, Jamie Wagner, Amanda L Amin, Kelsey E. Larson, Lawrence Ricci, Ossama Tawfik, Hana Razek, Ruby O Meierotto, Rashna Madan, Andrew K Godwin, Jeffrey Thompson, Andy Futreal, Alastair Thompson, Shelley Hwang, Fang Fan, On behalf of the Grand Challenge PRECISION consortium. Mouse-intraductal (MIND): The first in vivo model to recapitulate the full spectrum of human DCIS pathology [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD5-09.