Biomarkers to Target Heterogeneous Breast Cancer Stem Cells

Abstract

Breast cancer is the most common cancer and the second leading cause of death in U.S. women. Due to early detection and advanced treatment, the breast cancer death rate has been declining since 1990. However, disease recurrence is still the major obstacle in moving from therapy to truly curative treatments. Recent evidence has indicated that breast cancer recurrence is often caused by a subpopulation of breast cancer cells. This subset of cancer cells, usually referred to as breast cancer stem cells (BCSCs), exhibits stem cell phenotypes. They can self-renew and asymmetrically divide to more differentiated cancer cells. These cells are also highly resistant to conventional therapeutic reagents. Therefore, identifying and characterizing these BCSC subpopulations within the larger population of breast cancer cells is essential for developing new strategies to treat breast cancer and prevent recurrence. In this review article, we discuss the current proposed model for the origin of tumor heterogeneity, summarize the recent findings of cell surface and cytoplasmic markers for BCSC identification, review the regulatory mechanisms by which BCSCs maintain or non-cancer stem cells acquire BCSC characteristics, describe the proposed strategies to eliminate BCSCs, and highlight the current limitations and challenges to translate basic BCSC research to clinical application including establishment of clinical biomarkers and therapeutic treatments specifically targeting BCSCs.

Figure 1. A complex multidirectional relationship between differentiated cancer cells and heterogeneous BCSCs

Depending on genetic and epigenetic changes, miRNA and gene regulation or microenvironment stimuli, cancer cells are able to shift between stem-like and non-stemlike states. This plasticity contributes to the heterogeneity of BCSCs. The regulatory mechanisms underlying the shift from non-BCSCs to BCSCs also play important roles in maintaining the BCSC pool and its characteristics. The currently used cell surface markers for BCSC identification could be potentially useful clinical biomarkers.