Abstract

It is widely accepted that the cell of origin of breast cancer is the adult mammary epithelial stem cell; however, demonstrating the presence and location of tissue stem cells in the human breast has proved difficult. Furthermore, we do not know the clonal architecture of the normal and premalignant mammary epithelium or its cellular hierarchy. Here, we use deficiency in the mitochondrial enzyme cytochrome c oxidase (CCO), typically caused by somatic mutations in the mitochondrial genome, as a means to perform lineage tracing in the human mammary epithelium. PCR sequencing of laser‐capture microdissected cells in combination with immunohistochemistry for markers of lineage differentiation was performed to determine the clonal nature of the mammary epithelium. We have shown that in the normal human breast, clonal expansions (defined here by areas of CCO deficiency) are typically uncommon and of limited size, but can occur at any site within the adult mammary epithelium. The presence of a stem cell population was shown by demonstrating multi‐lineage differentiation within CCO‐deficient areas. Interestingly, we observed infrequent CCO deficiency that was restricted to luminal cells, suggesting that niche succession, and by inference stem cell location, is located within the luminal layer. CCO‐deficient areas appeared large within areas of ductal carcinoma in situ, suggesting that the rate of clonal expansion was altered in the premalignant lesion. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Highlights

  • The stem cell hierarchy of the human mammary epithelium has been the subject of much debate

  • Lineage tracing in murine models and in vitro studies have offered significant insight into the dynamics of stem cells in the mammary gland [1,28], but the translation of these findings to the normal human breast is uncertain

  • In this study, using a combination of histological and mitochondrial genetic analysis in human tissues, we obtained evidence that the human adult mammary epithelium is maintained by a population of multipotent stem cells

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Summary

Introduction

The stem cell hierarchy of the human mammary epithelium has been the subject of much debate. A recent study in human tissue combining a novel 3D fractal model approach with a theoretical model and with the expression of the putative stem cell marker high aldehyde dehydrogenase (ALDH1A1) has suggested that during morphogenesis of the mammary gland, the intralobular branching ducts are the site of cellular expansion and growth. This would indicate that this site may be the location of stem cells within the adult breast [11]. A novel analysis of multicolour lineage tracing at saturation during pubertal development of the mouse mammary gland rules out the presence and role of multipotent stem cells during adult tissue remodelling [12]

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