Mapping stem and progenitor cells to decipher the origins of breast cancer.

Breast cancer is a highly heterogeneous disease at both the molecular and pathologic levels. To understand this heterogeneity and the cells of origin of breast cancer, it is important to dissect the normal mammary epithelial hierarchy. Both transplantation and lineage tracing studies, a strategy for tracking stem and progenitor cell fate in situ, have been implemented to explore the contribution of stem and progenitor cells to postnatal mammary gland development and tissue homeostasis. The combination of lineage tracing with a novel three-dimensional imaging strategy, which enables visualization of large regions of intact tissue at cellular resolution, has provided insights into the normal differentiation hierarchy as well as potential cells of origin of breast cancer. In a further layer of investigation, we have applied single cell RNA-seq analysis to both mouse and human mammary tissue. This type of analysis has revealed unexpected heterogeneity among epithelial cells that reside in the normal mammary gland. In the context of human tissue, the identification of cells of origin of cancer and deregulated genes/pathways in crucial target cell populations may enable earlier detection of malignancies and lead to preventive therapies for individuals at high risk of developing breast cancer. Towards this end, we recently showed that the RANK receptor marks a small subset of luminal progenitors and this subset is expanded in precancerous tissue from BRCA1 mutation carriers. In preclinical Brca1 -deficient mouse models, inhibition of the RANK ligand (RANKL) prevented or delayed tumorigenesis. These data implicate blockade of the RANK-RANKL signaling axis as a promising breast cancer prevention strategy. Citation Format: Nai Yang Fu, Emma Nolan, Francois Vaillant, Rachel Joyce, Geoffrey Lindeman, Jane Visvader. Mapping stem and progenitor cells to decipher the origins of breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA02.