Abstract
The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin-DNA-RNA-protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor-positive and -negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology.
Highlights
The mammary gland is a defining feature of mammals
We classified genes based on their chromatin–DNA–RNA–protein relationships, quantifying the frequency and probability of specific states (Fig. 1 D and Table S2 for log-odds ratios and p-values)
Two-way comparisons confirm a positive association between open chromatin, RNA, and/or protein abundance
Summary
The mammary gland is a defining feature of mammals. Its study has provided new knowledge on organogenesis, differentiation programs, control of cell fate, and the molecular interplay that enables proliferation of tissue-specific progenitor cells (Hennighausen and Robinson, 2005). The mammary epithelial hierarchy has two main lineages, basal and luminal, each of which contain progenitor cells. Lineage-tracing studies have demonstrated that under physiological conditions, basal, ER+PR+ luminal, and ER−PR− luminal cells are each maintained by their own unipotent stem cells (Van Keymeulen et al, 2011, 2017; van Amerongen et al, 2012). Whether bipotent adult stem cells contribute to the mammary epithelium in a physiological setting is controversial. Some lineage-tracing studies have provided in situ evidence of bipotent stem cell activity (Rios et al, 2014; Wang et al, 2015), a subsequent statistics-based study has suggested that these results may result from a lack of labeling specificity (Wuidart et al, 2016), with questions remaining regarding both approaches (Rios et al, 2016)
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