Alexander Swarbrick1,2, Aranzazu Fernandez-Martinez3,4 and Charles M. Perou3,4 1Cancer Ecosystems Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia 2St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2052, Australia 3Lineberger Comprehensive Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA 4Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27514, USA Correspondence: a.swarbrickgarvan.org.au

Breast cancer is heterogeneous and differs substantially across different tumors (intertumor heterogeneity) and even within an individual tumor (intratumor heterogeneity). Gene-expression profiling has considerably impacted our understanding of breast cancer biology. Four main “intrinsic subtypes” of breast cancer (i.e., luminal A, luminal B, HER2-enriched, and basal-like) have been consistently identified by gene expression, showing significant prognostic and predictive value in multiple clinical scenarios. Thanks to the molecular profiling of breast tumors, breast cancer is a paradigm of treatment personalization. Several standardized prognostic gene-expression assays are presently being used in the clinic to guide treatment decisions. Moreover, the development of single-cell-level resolution molecular profiling has allowed us to appreciate that breast cancer is also heterogeneous within a single tumor. There is an evident functional heterogeneity within the neoplastic and tumor microenvironment cells. Finally, emerging insights from these studies suggest a substantial cellular organization of neoplastic and tumor microenvironment cells, thus defining breast cancer ecosystems and highlighting the importance of spatial localizations.