Abstract
There is accumulating evidence that breast cancer may arise from mutated mammary stem/progenitor cells which have been termed breast cancer-initiating cells (BCIC). BCIC identified in clinical specimens based on membrane phenotype (CD44+/CD24−/low and/or CD133+ expression) or enzymatic activity of aldehyde dehydrogenase 1 (ALDH1+), have been demonstrated to have stem/progenitor cell properties, and are tumorigenic when injected in immunocompromized mice at very low concentrations. BCIC have also been isolated and in vitro propagated as non-adherent spheres of undifferentiated cells, and stem cell patterns have been recognized even in cancer cell lines. Recent findings indicate that aberrant regulation of self renewal is central to cancer stem cell biology. Alterations in genes involved in self-renewal pathways, such as Wnt, Notch, sonic hedgehog, PTEN and BMI, proved to play a role in breast cancer progression. Hence, targeting key elements mediating the self renewal of BCIC represents an attractive option, with a solid rationale, clearly identifiable molecular targets, and adequate knowledge of the involved pathways. Possible concerns are related to the poor knowledge of tolerance and efficacy of inhibiting self-renewal mechanisms, because the latter are key pathways for a variety of biological functions and it is unknown whether their interference would kill BCIC or simply temporarily stop them. Thus, efforts to develop BCIC-targeted therapies should not only be focused on interfering on self-renewal, but could seek to identify additional molecular targets, like those involved in regulating EMT-related pathways, in reversing the MDR phenotype, in inducing differentiation and controlling cell survival pathways.
Highlights
Advances over the last decades in diagnosis and treatment have resulted, since the early nineties, in decreased mortality, breast cancer remains the most common malignant disease in Western women
Such studies should increase knowledge of the molecular mechanisms involved in breast tumor initiation and progression and determine the relevance of particular signal transduction pathways to self renewal, in order to relate the presence of breast stem/progenitor cell phenotypes to existing subclassifications of breast cancer and to patient outcome and to identify novel therapeutic targets
Stem cell-like cancer cells isolated by distinct approaches from established breast cancer cell lines have been considered as surrogate models of cultures of tumor-initiating cells derived from clinical tumors or of direct xenografts of surgical tumor specimens in immunocompromized animals
Summary
Advances over the last decades in diagnosis and treatment have resulted, since the early nineties, in decreased mortality, breast cancer remains the most common malignant disease in Western women. /or growing as nonadherent spheres and on engraftment of clinical tumors directly into immunocompromized mice, to propagate in vivo highly tumorigenic cells Such approaches are instrumental for the functional validation of new targets identified on clinical tumors through analysis of the consequences of their down-regulation by specific inhibitors on breast cancer stem/progenitor cell properties and for assessing the effect of epigenetic modulation-based approaches on self-renewal capacities. Such studies should increase knowledge of the molecular mechanisms involved in breast tumor initiation and progression and determine the relevance of particular signal transduction pathways to self renewal, in order to relate the presence of breast stem/progenitor cell phenotypes to existing subclassifications of breast cancer and to patient outcome and to identify novel therapeutic targets. We reviewed studies published in the last few years addressed to investigate the biological properties of BCIC, the role of stemness-related markers on breast cancer progression, and the relevance of BCIC features/experimental systems for cancer therapy, in terms of association with clinical response to systemic treatments and identification of new potential therapeutic targets
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