Breast cancer stem cells: A review of their characteristics and the agents that affect them

Abstract

The evolving concept that cancer stem cells (CSCs) are the driving element in cancer development, evolution and heterogeneity, has overridden the previous model of a tumor consisting of cells all with similar sequentially acquired mutations and a similar potential for renewal, invasion and metastasis. This paradigm shift has focused attention on therapeutically targeting CSCs directly as a means of eradicating the disease. In breast cancers, CSCs can be identified by cell surface markers and are characterized by their ability to self-renew and differentiate, resist chemotherapy and radiation, and initiate new tumors upon serial transplantation in xenografted mice. These functional properties of CSCs are regulated by both intracellular and extracellular factors including pluripotency-related transcription factors, intracellular signaling pathways and external stimuli. Several classes of natural products and synthesized compounds have been studied to target these regulatory elements and force CSCs to lose stemness and/or terminally differentiate and thereby achieve a therapeutic effect. However, realization of an effective treatment for breast cancers, focused on the biological effects of these agents on breast CSCs, their functions and signaling, has not yet been achieved. In this review, we delineate the intrinsic and extrinsic factors identified to date that control or promote stemness in breast CSCs and provide a comprehensive compilation of potential agents that have been studied to target breast CSCs, transcription factors and stemness-related signaling. Our aim is to stimulate further study of these agents that could become the basis for their use as stand-alone treatments or components of combination therapies effective against breast cancers.

Keywords: breast cancer; cancer stem cells; differentiation; pluripotency.

Figure 1.. Breast cancer stem cell signaling, transcription factors and agents that target them.

Agents targeting the self-renewal program controlled by transcription factor mediators, OCT4, SOX2, NANOG or KLF4, agents reducing stemness by targeting aberrantly activated signaling pathways involving Notch, Wnt, Hh, STAT3 or TGF-β, and agents inducing differentiation of breast cancer stem cells by reprogramming cells into more differentiated tumor cells are to be exploited in treatment and prevention of breast cancer.