Send Orders for Reprints to reprints@benthamscience.ae 256 Current Cancer Drug Targets, 2015, 15, 256-269 Cancer Stem Cells in Solid and Liquid Tissues of Breast Cancer Patients: Characterization and Therapeutic Perspectives Rena Chiotaki, Hara Polioudaki and Panayiotis A. Theodoropoulos * Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece Abstract: Breast cancer stem cells (BCSCs) represent a heterogeneous subpopulation of rare cells within breast cancer tumors, displaying an enhanced tumor initiating capability and underlying disease progression and therapy resistance. Unraveling their phenotypic, biological and functional profile is a major challenge in the context of diminishing patient mortality. In this review, following a brief description on how cancer stem cells (CSCs) and their microenvironment contribute to tumor preservation and heterogeneity, we summarize the current literature regarding the molecular signature of BCSCs either localized in the primary tumor or circulating in the blood of breast cancer patients. We present recent data on specific stem and epithelial-to-mesenchymal transition (EMT) markers designating the BCSC subpopulation and underline their pathogenic significance. The molecular characterization of BCSCs has promoted the design of novel therapeutic approaches targeting the BCSC subpopulation which are currently being experimentally and clinically evaluated. We highlight recent advances on the development of novel BCSC-targeting therapeutic strategies including the inhibition of cell signaling pathways, differentiation therapy, metabolic interference and nucleotide-, bio- and nano-technology based approaches. Eliminating the chemo- and radio-resistance properties of breast cancer tumor cells via BCSC-directed therapies, combined to conventional therapeutic approaches, will augment the effectiveness of breast cancer treatment and improve the clinical outcome of breast cancer patients. Keywords: Breast cancer, cancer stem cells, circulating tumor cells, epithelial-to-mesenchymal transition, targeting of cancer stem cells. INTRODUCTION The existence of CSCs was originally demonstrated twenty years ago, when research in the field of blood cancer revealed [1] that a cell exhibiting the CD34 + /CD38 - phenotype initiates acute myeloid leukemia after transplantation into SCID mice. Not many years later, a pioneering study [2] confirmed that CSCs can also be identified in breast cancer solid tumors and demonstrated that a small subpopulation of BCSCs bearing the molecular signature CD44 + /CD24 -/low /Lin - initiated tumor formation when implanted into immunodeficient NOD/SCID mice. In a series of following studies, the identification and characterization of CSCs with tumor generating capacity, also designated as tumor initiating cells, tumor propagating cells or cancer initiating cells, progressed in the area of brain [3], liver [4], colorectal cancer [5] and melanoma [6, 7]. In addition to the origination and preservation of the neoplastic tissue, CSCs are also implicated in metastasis formation, the main cause of decease among cancer patients (reviewed in [8]). In order for cancer cells to disseminate from a primary tumor mass and enter the bloodstream, they have to acquire mesenchymal features, promoting their motility and invasiveness, via their engagement into an EMT genetic program. Circulating tumor cells (CTCs) in the blood of cancer patients have long been considered to be the source of metastasis, the major cause of *Address correspondence to this author at the University of Crete, School of Medicine, P.O. Box 2208, 71003 Heraklion, Greece; Tel: +30 2810 394546; Fax: +30 2810 3945430; E-mail: takis@med.uoc.gr treatment failure and mortality in cancer patients and are proposed to have clinical utility in all cancers of epithelial origin ([9] and references therein). The use of liquid biopsies, non-invasive blood tests that enable the detection of CTCs and free nucleotide (DNA or RNA) fragments [10- 16], has offered valuable insight into tumor diagnosis and treatment. The induction of EMT has been shown to generate undifferentiated cells with CSC properties [17-20], thus providing a link between EMT and cancer cell stemness. Over the last years, a plethora of review and research articles have emerged on the rapidly evolving field of CSC biology. Although the role of CSCs in breast cancer, one of the leading causes of mortality among women, has been thoroughly highlighted in many stimulating studies, collective data on the expression of EMT and stem cell markers on both primary breast cancer tumors and breast cancer CTCs (BCTCs) are rather lacking. In this review, we will summarize the current knowledge regarding the molecular characterization of BCSCs based on data extrapolated from the study of both solid tumors and BCTCs (Fig. 1) and we will describe recent advances on the development of novel anti-cancer strategies specifically targeting the BCSC subpopulation. THE CONTRIBUTION OF CSCs AND MICRO- ENVIRONMENT IN TUMOR PRESERVATION AND HETEROGENEITY CSCs are identified based on their capability of self- renewing, differentiating, forming and sustaining tumors in mice and propagating as non-adherent tumorspheres ex vivo 1873-5576/15 $58.00+.00 © 2015 Bentham Science Publishers