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There are currently two fundamental questions facing cancer biologists, the first being the cell-of-origin of cancer, i.e. did the tumor in a specific patient arise from the transformation of stem cells or more differentiated progeny? Understanding the cellular etiology of cancer may help interpret the clinical manifestation of tumor phenotypes (e.g. those observed by pathologists) and stratify patients into appropriate treatment groups. The second question is whether cancer cells in a clinical tumor are functionally distinct and lineage related. The answer to this question holds clear clinical significance because, although the current targeted therapy and precision medicine emphasize corrupted molecular targets, it is the cancer cells that are being treated. If cancer cells are heterogeneous in expressing the therapeutic target(s), those that do not express the target(s) will not respond well or at all. In the past two decades, research has demonstrated that in most, if not all, human cancers, there exists a dynamically evolving population of cancer cells that possess at least some inherent properties of normal stem cells. These stem-like cancer cells, operationally dubbed as cancer stem cells (CSCs), are endowed with high tumor-regenerating and tumor-propagating capacities and, in many cases, have been shown to selfrenew and generate more differentiated non-CSC progeny (Kreso & Dick, 2014). Recent lineage tracing studies in genetically-engineered mouse models (GEMMs) have provided further evidence for CSCs (Chen et al. 2012, Driessens et al. 2012, Schepers et al. 2012). This thematic issue of ‘Stem Cells and Cancer’ is dedicated to breast and prostate cancers, which share many similarities (Risbriger et al. 2010). The mammary and prostatic glands are both organized primarily as twolayered, pseudostratified glandular structures with a differentiated luminal layer expressing steroid hormone receptors (ER, PR, AR, etc) and a basal or myoepithelial (for breast) cell layer expressing transcription factor p63 but not steroid hormone receptors. The tumors in both organs present mainly as a luminal phenotype in that most tumor cells express steroid hormone receptors (Fig. 1). Consequently, inhibition of steroid hormone signaling via blocking receptor function and hormone synthesis represents the major clinical intervention in both cancers. In this issue, five leading groups in the field discuss the cells of origin and CSCs in breast and prostate cancers, expounding on the potential clinical relevance. Sreekumar et al. (2015) present a comprehensive, up-to-date, overview on the complex hierarchy of murine mammary stem cells (MaSCs). Multiple populations of adult MaSCs have been reported including CD29 CD24/CD49, s-SHIP, label-retaining cells, CD1d, Procr, Axin2, CD61 and Lgr5 cells. Lineage tracing studies show that the basal cell layer harbors both unipotent progenitors (K5, K14, aSMA) and bipotent (some K5, Procr, and Axin2) stem cells whereas luminal progenitor cells are unipotent as the K8 luminal cells have never been observed to give rise to basal cells in vivo in the normal mammary gland. Basal MaSCs and most luminal progenitor cells are ERa/PR. Interestingly, in a basal-like breast cancer model induced by Brca1 loss, luminal progenitors are likely the cell of origin for the tumors, suggesting that luminal cells may be reprogrammed to undergo basal-like transdifferentiation by oncogenic insults. Breast cancer is the first human solid tumor in which evidence for CSCs was presented (Al-Hajj et al. 2003). By now, multiple populations of breast cancer stem cells (BCSCs) have been reported including CD44CD24 and ALDH populations as well as side population (SP) and

Cancers of the breast and prostate: a stem cell perspective