The Cancer Stem-Cell Hypothesis of Breast Cancer

Hypotheses regarding the development of malignant diseases are tightly linked to the physiology of organogenesis. This observation has been summarized by Van R. Potter in the British Journal of Cancer making the paradigmatic statement: „Oncogenesis is a partially blocked ontogenesis“ [1]. The female breast is an extremely dynamic organ and this observation can be supported by the extensive structural changes during pregnancy and lactation [2]. Therefore the existence of a mammary epithelial stem-cell as a pivot of specific physiological and pathophysiological changes might be obvious. Several investigations support the existence of such a pluripotent cell type, but a commonly accepted characterization in humans is still pending. Due to this fact there are several „stem-cell markers“ used which are associated with the putative stem cell. In this context Boecker [3] and Ellis [4] suggested, that the mammary epithelial stem-/progenitor cell can be characterized as a CK5/14+ subtype. Based on this immature phenotype glandular/luminal (CK5/14+, CK8/18+) or myoepithelial (CK5/14+, p63, smActin) precursor cells will develop towards a mature ductal/lobular and myoepithelial type of cells. However, it still remains unclear which factors contribute to specific differentiation steps and when stem- or progenitor cells will become endocrine responsive. Currently it is supposed that two different populations of stem-/progenitor cells might exist: one type is long-living, quiescent, ER negative and the other short-living, ER positive, which can be stimulated by estrogen during puberty/pregnancy and constitutes an ER negative „transient amplifying“ subpopulation in the presence of estrogens [5,6]. In this context it is important to distinguish between two conceptions: on the one hand several investigations could demonstrate that within a heterogeneous tumor cells can be detected sharing stem-cell like properties. The proliferative activity of these cells seems to be responsible for tumor growth (stem cells of the tumor). Moreover there is evidence from gene expression analysis that there are bulk cancers sharing phenotypical properties, which resemble immature (basal) cell types (stem cell-like tumors). The phenotyping of tumor stem cells is somewhat difficult, since only 1–10% of all tumor cells can be attributed to stem cells [7]. In contrast there is evidence that cancer development is associated with a blockade of differentiation („maturation arrest theory“) [8]. This theory indicates that genetic alterations can occur in different cell types (stem-/progenitor cells and differentiated cells) leading to uncontrolled proliferation and tumors sharing phenotypical properties of the primary cell.

The clinical implications of both concepts are numerous. Thus it could be demonstrated that a stem cell-like subpopulation (CD24^low/CD44⁺) derived from the MCF-7 line shows a significant higher resistance to irradiation [9]. Balic et al. provided evidence that 71% of disseminated tumor cells have a stem cell-like phenotype (CK⁺/CD24^-) [10]. The cellular compartment of BRCA-1/2 mutation is still a matter of debate. Palacios et al. showed that breast cancers with a BRCA-1 mutation have stem cell-like features [11].

Microarray analysis allows an analysis of coordinated expression of known and the detection of putative stem cell markers resulting in a new classification of breast cancers according to a biological model [12]. The existence of ER positive and negative stem- and progenitor subpopulations has been discussed for a long period[5,6]. In this context both subpopulations with a distinct ER status display a unique framework, which enables analysis of specific characteristics of ER pathways. By means of unsupervised cluster analysis it is possible to identify two subtypes of breast cancers exhibiting already known stem cell markers (e.g. CK-5, -6, -14, -17, ITGA6, S100A1, CD24, as well as members of NOTCH and WNT pathways) [12]. However, both subtypes differ in ER status and proliferative activity. This inverse correlation is nearly perfectly detectable in breast cancers with stem cell-like features but abolished in ER positive tumors with non-stem cell-like properties representing a proportion of 30% of all samples. These tumors can be characterized by a high proliferation despite their positive ER status and the clinical course of disease is impaired even when comparing with high proliferative ER negative breast cancers. Standard parameters as ER status and proliferation can be linked with a new context by using such a classification. Therefore different subgroups can be defined which allows the verification of molecular dysregulations and the identification of new predictive and prognostic markers as well as new possible therapeutic targets [13].

Moreover it could be demonstrated that clinically relevant subgroups can be identified when using differentially expressed genes after re-programming of somatic cells into pluripotent cells („induced pluripotent stem cells“ by transfection with Oct3/4, Sox2, c-Myc and Klf4) [14]. These subgroups differ in terms of ER status, proliferation, expression of stem cell markers and prognosis significantly [15]. In conclusion all these data suggest that the stem cell concept of breast cancer is far from being a hypothetical construct, but seems to be an attractive and clinically relevant model, which gives new insight in origin, development and course of disease and could be helpful in identifying new therapeutic targets.

References:

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