Breast Cancer Stem Cell Membrane Biomarkers: Therapy Targeting and Clinical Implications

Abstract

Breast cancer is the most common malignancy affecting women worldwide. Importantly, there have been significant improvements in prevention, early diagnosis, and treatment options, which resulted in a significant decrease in breast cancer mortality rates. Nevertheless, the high rates of incidence combined with therapy resistance result in cancer relapse and metastasis, which still contributes to unacceptably high mortality of breast cancer patients. In this context, a small subpopulation of highly tumourigenic cancer cells within the tumour bulk, commonly designated as breast cancer stem cells (BCSCs), have been suggested as key elements in therapy resistance, which are responsible for breast cancer relapses and distant metastasis. Thus, improvements in BCSC-targeting therapies are crucial to tackling the metastatic progression and might allow therapy resistance to be overcome. However, the design of effective and specific BCSC-targeting therapies has been challenging since there is a lack of specific biomarkers for BCSCs, and the most common clinical approaches are designed for commonly altered BCSCs signalling pathways. Therefore, the search for a new class of BCSC biomarkers, such as the expression of membrane proteins with cancer stem cell potential, is an area of clinical relevance, once membrane proteins are accessible on the cell surface and easily recognized by specific antibodies. Here, we discuss the significance of BCSC membrane biomarkers as potential prognostic and therapeutic targets, reviewing the CSC-targeting therapies under clinical trials for breast cancer.

Keywords: breast cancer stem cells; cell membrane biomarkers; targeted therapies; translational oncobiology.

Figure 1

Main features of CSC biology: cell of origin, plasticity, and their role in metastasis. CSCs are characterized by their self-renewal and differentiation capacities, which confers them the ability to form/repopulate heterogeneous cancer cell populations. Moreover, due to their enhanced mechanisms of chemo- and radioresistance, CSCs are considered as the main responsible for tumour recurrence and metastases. Generally, CSCs divide asymmetrically, giving rise to a CSC and a differentiated cell that integrates with tumour bulk. However, under stress conditions, as cell loss during anticancer treatment, they can also divide symmetrically, originating two CSCs, which allows the excessive promotion of tumour growth and repopulation. Biorender: https://biorender.com (accessed on 12 January 2022).

Figure 2

CSC resistance to conventional chemotherapy and the potential of CSC-targeting therapies for tumour eradication. The conventional chemotherapy that is currently in clinical practice targets highly proliferative cells and is ineffective against CSCs, which will ultimately be responsible for tumour relapses. The combination of standard chemotherapy with CSC-targeting therapies might be a promising strategy for tumour eradication. Biorender: https://biorender.com (accessed on 4 September 2021).

Figure 3

Breast cancer stem cell membrane biomarkers, signalling pathways, and targeting therapies in clinical trials. CD44, integrin alpha 6, EpCAM, Cadherin 3, HER2, prominin-1, and CXCR1 are commonly recognised as CSC membrane biomarkers, whose expression has been associated with breast cancer. Bivatuzumab mertansine is a CD44v6-targeted therapy that has been tested in phase I clinical trials in anthracycline and taxane pretreated patients with metastatic breast cancer who were shown to have CD44v6 expression. Adecatumumab is an EpCAM-targeting antibody already in phase II clinical trials; however, it does not have a significant impact on EpCAM overexpressing breast cancer patients. PCA062, Y-FF-21101, and PF-06671008 are molecules that specifically target cadherin-3 that are currently in clinical trials. Trastuzumab and lapatinib are drugs already in clinical practice as HER2-targeted therapies, which emerging studies describe as contributing to BCSC elimination. Repaxirin is in phase II clinical trials for CXCR1 inhibition, showing interesting results in the reduction in BCSC content. Since Wnt–β-catenin, Hh, and Notch signalling are associated with self-renewal, differentiation, apoptosis, and survival, they are usually upregulated in cancer and are, therefore, seen as promising for CSC-targeting therapies. In particular, for breast cancer, the CSC-targeting therapies in clinical trials have CSC signalling pathways as their main targets. Specifically, vantictumab is a Wnt inhibitor, sonidegib and vismodegib are SMO inhibitors, and MK-0752, nirogacestat, and RO4929097 are γ-secretase inhibitors. Biorender: https://biorender.com (accessed on 9 November 2021).