Transcriptional regulation of normal human mammary cell heterogeneity and its perturbation in breast cancer

Abstract

The mammary gland in adult women consists of biologically distinct cell types that differ in their surface phenotypes. Isolation and molecular characterization of these subpopulations of mammary cells have provided extensive insights into their different transcriptional programs and regulation. This information is now serving as a baseline for interpreting the heterogeneous features of human breast cancers. Examination of breast cancer mutational profiles further indicates that most have undergone a complex evolutionary process even before being detected. The consequent intra-tumoral as well as inter-tumoral heterogeneity of these cancers thus poses major challenges to deriving information from early and hence likely pervasive changes in potential therapeutic interest. Recently described reproducible and efficient methods for generating human breast cancers de novo in immunodeficient mice transplanted with genetically altered primary cells now offer a promising alternative to investigate initial stages of human breast cancer development. In this review, we summarize current knowledge about key transcriptional regulatory processes operative in these partially characterized subpopulations of normal human mammary cells and effects of disrupting these processes in experimentally produced human breast cancers.

Keywords: breast cancer; chromatin; epigenomics; mammary; transcriptional regulation.

Figure 1. Macro‐ and microscopic structure of the normal human breast

(A) Diagram showing the macroscopic structure of the human breast and histological sections of ducts and alveoli (scale bar = 100 μm). (B) Effects of serum hormone levels on the human mammary epithelium during the menstrual cycle.

Figure 2. Subpopulations of cells within the normal adult human mammary gland

(A) Diagram showing the workflow for separating the four main cell populations present in the breast in addition to blood cells and endothelial cells (scale bar = 400 μm). (B) Examples of typical Giemsa‐stained colonies derived from BCs and LPs and assessed after 7–9 days in vitro (scale bar = 400 μm).

Figure 3. Transcriptional regulation of normal human mammary cell subpopulations

(A) TF regulatory networks constructed from the chromatin profiles at enhancers of BCs, LPs, and LCs. (B) Genome browser plots showing the differences in chromatin states defined for normal human mammary cell subpopulations and non‐tumorigenic mammary cell lines around the PROM1 and the NT5E genes.

Figure 4. Transcriptional regulators active in the normal human mammary gland and in human breast cancer

(A) Ternary plot of relative expression of all transcriptional regulators in normal human mammary cell subpopulations from a re‐analysis of the RNA‐seq data presented in Pellacani et al (2016). Transcriptional regulators discussed in the text are highlighted. (B) List of the top 20 transcriptional regulators most specific to each cell type highlighted in (A). (C) Clustering of the tumors profiled by RNA‐seq in Nik‐Zainal et al (2016) using the genes shown in (B).

Figure 5. Frequency of genomic alteration of GATA3, MYC, FOXA1, and KMT2C in human breast cancer subtypes

Heatmap showing the frequency of genomic alterations detected in GATA3, MYC, FOXA1, and KMT2C in human breast cancer subtypes. Data are drawn from the 993 breast cancer cases in the TCGA PanCancer Atlas study analyzed and plotted via cBioportal (http://www.cbioportal.org).