Cancer Stem Cells as Attractive Targets for Breast Cancer Therapy

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About this Research Topic

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Background

Breast cancer is the second leading cause of cancer-related death among females worldwide. It is a complex heterogeneous disease and can be classified into different molecular subtypes according to the expression of estrogen or progesterone receptors and human epidermal growth factor 2 (Her-2). Based on the molecular subtypes and the proliferative index Ki-67, decisions for treatment regimes can be determined including surgery, chemotherapy, radiotherapy, endocrine therapy, and targeted therapy. Tumor metastasis and recurrence are still the major challenges for the current therapeutic modalities used for patients with breast cancer.

The tumor bulk is comprised of differentiated cells and a subset of cells with stem cell properties known as cancer stem cells (CSCs). This subpopulation can be identified by the expression of specific markers by which they can be distinguished from cancer cells, e.g., CD133, CD44, CD24, and ALDH-1. Breast CSCs can be identified by expression of the cell surface marker CD44 and CD24 as a CD44(positive)/CD24(negative/low) subset. Several studies indicate that CSCs can be generated via induction of epithelial-mesenchymal transition (EMT) program in epithelial cells. Of note, mounting evidence indicates conversion from EMT to MET is required to revert CSCs from metastatic (for dissemination) into proliferative phenotype to form metastatic colonies. Distant metastasis, development of resistance to conventional therapies, and tumor recurrence are essentially attributed to the enrichment of CSCs. Therefore, CSCs emerge as attractive targets to overcome drug resistance and enhance sensitization to chemo and radiotherapy.

In breast cancer, it has been reported that CSCs express immune markers, such as the co-inhibitory molecule and immune checkpoint ligand programmed death-ligand 1 (PD-L1), which upregulate expression of transcription factors OCT4, and Nanog involved in CSC regulation. Indeed, this exploiting this expression pattern could be used to develop breast CSC-centered immunotherapy. Several signaling pathways are known to regulate breast CSC phenotype, namely IL-6/STAT3/NFkB, Notch, Hedgehog, and Wnt/β-catenin pathways. Furthermore, genetic mechanisms, epigenetic factors (including microRNAs and long non-coding RNAs), hormones, and tumor microenvironmental components can also regulate breast CSCs. Therefore, combinatorial therapeutic strategies could be employed to target specific markers or properties of breast CSCs.

Our aim in this Research Topic is to introduce new markers and druggable targets, as well as elucidation of molecular mechanisms underlying breast CSC functions. This may contribute to opening new avenues to curtail breast cancer metastasis and tumor relapse. We welcome Original Research Articles, Reviews, and Mini-Reviews. Topics of interest include:

• CSCs in breast cancer metastasis

• EMT and MET plasticity in breast CSCs

• Role of epigenetic mechanisms in the regulation of breast CSCs

• Role of hormones in the regulation of breast CSCs

• Crosstalk between tumor microenvironmental cells and breast CSCs.

• Signaling pathways involved in breast CSC regulation

• New (pharmacological) inhibitors to target breast CSCs

Keywords: Cancer stem cells, cancer initiating cells, breast cancer, metastasis, EMT, chemotherapy, radiotherapy, tumor microenvironment, non-coding RNA

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