Therapeutic Implications of Cellular Heterogeneity and Plasticity in Breast Cancer

Abstract

Cellular heterogeneity represents one of the greatest challenges in cancer therapeutics. In many malignancies, this heterogeneity is generated during tumor evolution through a combination of genetic alterations and epigenetic events that recapitulate normal developmental processes including stem cell self-renewal and differentiation. Many, if not most, tumors display similar hierarchal organization, at the apex of which are "stem-like cells" that drive tumor growth, mediate metastasis, and contribute to treatment resistance. Using breast cancer as a model, we discuss how an improved understanding of tumor cellular heterogeneity and plasticity may lead to development of more effective therapeutic strategies.

Figure 1

Cellular Heterogeneity and Plasticity in Breast Cancer. Recent work has identified two distinct types of cancer stem cells in breast cancer, a mesenchymal, quiescent type marked by being CD44+/CD24− (EMT-CSCs) and an epithelial, proliferative type identified as ALDH+ (MET-CSCs). A double positive CD44+/CD24−/ALDH+ population with even higher tumorigenicity exists, but it is yet to be determined if this is a stable or transient population. The transition between these states is common in vitro and is likely to be regulated by multiple cell types in the tumor microenvironment through IL8, Notch, and GH (growth hormone) signaling as well as paracrine interactions between CSCs and their more differentiated progeny. Derived from these two CSC states are two differentiated bulk tumor cell types; a epithelial type produced by MET-CSCs (common in most of the molecular subtypes) and a group of mesenchymal bulk tumor cells derived from EMT-CSCs (rare in the majority of breast cancer cases, but common in the claudin-low molecular subtype). Among the corollaries of this model is the idea that the probability of dedifferentiation is not uniform, but is instead inversely proportional to the number of cellular divisions removed from being a cancer stem cell. Furthermore, mutation in CSCs generate new CSCs as well as clones of differentiated progeny generating cellular heterogeneity during tumor evolution.

Figure 2

Model illustrating variations in CSCs and their differentiated progeny across the spectrum of breast cancer subtypes. In this model, the different molecular subtypes of breast cancer are characterized by varying proportions of CSCs in mesenchymal (EMT) versus epithelial (MET) states as well as differential blocks in the differentiation hierarchy seen in normal mammary development.

Figure 3

Strategy for combining CSC targeting agents with approved drugs that target the bulk tumor populations in each molecular breast cancer subtype. The diagram on left illustrates CSC targeting drugs either approved or in development and, on the right, FDA approved drugs to treat each of the molecular subtypes of breast cancer.