Keeping an open mind: highlights and controversies of the breast cancer stem cell theory

Figures & data

Figure 1 Models explaining the origins of tumor heterogeneity in breast cancer.

Notes: Tumor heterogeneity (middle) is due to cancer cell types differing in genetic and phenotypic identities, as well as differing in terms of spatial and temporal existence within the tumor. These variations can depend on genetic insults and epigenetic alterations induced by microenvironmental changes. The two models explain the origin of this heterogeneity: the clonal evolution and the BCSC theory. The clonal evolution model (left) proposes that cancer clones compete with each other and the microenvironment to expand and dominate within the tumor (eg, Clone 1, 2, 3, and 4). Some clones may expand, but do not evolve fast enough to survive selective pressures and die off (Clone 5). A genetic drift of a single clone can generate a subclone (Clone 1.1). The BCSC model (right) proposes that BCSCs arise from transformed mammary cells. These BCSC self-renew (arced arrow), and give rise to highly proliferating progenitor cells that are responsible for generating differentiated cancer cells within the tumor.
Abbreviation: BCSC, breast cancer stem cell.

Figure 2 Proposed model of the human MaSC differentiation hierarchy with corresponding surface markers for stem/progenitor cell identification and isolation.

Note: A possible relationship to the cellular origin of breast cancer subtypes is shown in Table 1.
Abbreviation: MaSC, mammary stem cell.

Figure 3 Unified theory of tumor heterogeneity.

Notes: The dynamic nature of tumor initiation and progression is characterized by genetic and epigenetic insults on putative cancer cells and the microenvironment. The heterogeneity of the microenvironment includes varying densities of extracellular matrix, vasculature, immune cells, and oxygen concentration that places selective pressure on cancer cells. The genetic and epigenetic make-up of cells within tumors will vary from one region to the other. Some regions may be characterized by a BCSC hierarchy (A), stochastic plasticity (B), and clonal evolution (C) simultaneously, increasing its complexity.
Abbreviations: BCSC, breast cancer stem cells; ECM, extracellular matrix.

Table 1 Biological and clinical characteristics of breast cancer molecular subtypes

Subtype	Markers	Prevalence	CSC enrichment	Targeted treatment	Mechanism	Prognosis
Luminal A	Mostly ER^+ and/or PR^+ (some HER2^+)	42%–59%	Low	Tamoxifen	ER	Good
Luminal B	Mostly ER^+ and/or PR^+ (some HER2^+) Highly proliferative	6%–19%	Intermediate	Tamoxifen, Herceptin	ER, HER2	Intermediate
HER2^+	HER2^+ (can be ER^+/ER^− and PR^+/PR^−)	7%–12%	High	Lapatinib, Herceptin	HER2	Poor
Basal-like triple negative	Mostly ER^−/PR^−/HER2^−, CK5^+/6^+, and/or HER1^+	14%–20%	High	Bevacizumab, PARP inhibitors	HER1	Poor

Abbreviations: ER, estrogen receptor alpha; PR, progesterone receptor; HER2, epidermal growth factor receptor 2; HER1, epidermal growth factor receptor 1.