Abstract 989: Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages and can form chimeric mammary glands in vivo

Abstract Use of cell culture models to investigate the development of cancer associated with familial breast cancer syndromes is challenging because many culture methodologies do not maintain all of the lineages that are present in vivo, particularly the progenitor cells that may be the specific cancer cell-of-origin. We evaluated the ability of organoid culture technology to preserve stem/progenitor and differentiated cell types via long-term propagation of normal human mammary tissues. Tissue samples were obtained from elective reduction mammoplasties or from prophylactic mastectomies for cancer prevention, and were histologically normal. These were grown using conditions similar to organoid cultures for other epithelial cell types, as has been recently described (Sachs et al., Cell 2018). We found that basal stem and luminal progenitor cells could be cultured long-term, and differentiated in culture to generate mature basal and luminal cell types. Analysis of matched organoid cultures and native tissues by mass cytometry (CyTOF) for 38 markers at single-cell resolution confirmed the presence of multiple mammary epithelial cell types in the organoids, and demonstrated that protein expression patterns of the tissue of origin were largely preserved in culture. In addition, we generated a panel of over 40 mammary organoids derived from patients harboring inherited mutations in the cancer predisposition gene BRCA1 and from unaffected controls. Despite interindividual variability, an expansion in luminal progenitor populations associated with BRCA1 mutation could be detected in cultured organoids. Human mammary organoids heterozygous for BRCA1 could be engrafted into the murine mammary gland, resulting in mixed ductal and acinar structures. These studies indicate that this new model system is well suited for studies of aberrant phenotypes associated with BRCA1 mutation and approaches to prevent cancer development in these genetically predisposed tissues. Citation Format: Jennifer M. Rosenbluth, Ronald Schackmann, Carman Li, Norman Sachs, Deborah Dillon, Andrea Richardson, Jane Brock, Judy Garber, Gary Kenneth Gray, Jason Zoeller, Mackenzie Boedicker, Hendrick Johannes Kuiken, Hans Clevers, Joan Brugge. Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages and can form chimeric mammary glands in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 989.