Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention

Abstract

Breast cancer prevention is daunting, yet not an unsurmountable goal. Mammary stem and progenitors have been proposed as the cells-of-origin in breast cancer. Here, we present the concept of limiting these breast cancer precursors as a risk reduction approach in high-risk women. A wealth of information now exists for phenotypic and functional characterization of mammary stem and progenitor cells in mouse and human. Recent work has also revealed the hormonal regulation of stem/progenitor dynamics as well as intrinsic lineage distinctions between mammary epithelial populations. Leveraging these insights, molecular marker-guided chemoprevention is an achievable reality.

Keywords: breast cancer prevention; cell-of-origin; high-risk women; mammary stem and progenitors; progesterone.

Figure 1. The breast: structure, risk factors and stages of cancer development

(A) Schematic of the human breast highlighting terminal ductal lobular units (TDLUs), the site of origin in a number of breast cancers. (B) Some of the major risk factors underlying high‐risk status for breast cancer. (C) Schematic of a ductal cross‐section, depicting the progression of breast cancer from normal bi‐layered epithelium to hyperplasia, to hyperplasia with atypia, to ductal carcinoma in situ, and finally to invasive disease.

Figure 2. Progesterone‐driven cellular and molecular changes in the mammary gland

(A) The murine estrous cycle is shown with mammary whole mounts depicting the gross morphological changes elicited by fluctuations in the ovarian hormones, estrogen, and progesterone. The corresponding expansion in mammary stem and progenitors is also highlighted. Schematic illustrates the strategy of utilizing factors that limit stem/progenitor expansion as chemopreventive agents in breast cancer. Ulipristal acetate is a selective progesterone receptor modulator, and denosumab is an anti‐RANKL agent. (B) Schematic of key mitogenic paracrine effectors downstream of progesterone in the breast, some of which may prove effective as targets in future breast cancer chemoprevention strategies.

Figure 3. Lineage‐specific molecular programs and epigenetic regulators

(A) Schematic illustrating the main GO terms biological processes (≥ 3‐fold upregulated, FDR ≤ 0.01) enriched in the three distinct mammary cell subpopulations in response to progesterone, based on proteomic analysis from Casey et al. (B) Visualization of the indicated epigenetic proteins or histone marks (green) in situ. Lineage specificity is observed for select proteins (EZH2, DNMT1, and SETD7). Cytokeratin 5 (red) marks the basal compartment. (C) Comparative abundance of epigenetic regulatory proteins detected in luminal vs. basal compartment.

Figure 4. A path to OMICS‐guided chemoprevention

A workflow modeling a discovery‐to‐intervention pipeline for OMICs‐guided chemoprevention. FACS‐purified mammary cell populations are the input for integrative molecular profiling, target validation, rationalized drug identification, and evaluation in a series of biological, pre‐clinical assays.