Abstract
BackgroundBreast cancer stem cells (BCSCs) are the source of breast tumors. Compared with other cancer cells, cancer stem cells show high resistance to both chemotherapy and radiotherapy. Targeting of BCSCs is thus a potentially promising and effective strategy for breast cancer treatment. Differentiation therapy represents one type of cancer stem-cell-targeting therapy, aimed at attacking the stemness of cancer stem cells, thus reducing their chemo- and radioresistance. In a previous study, we showed that down-regulation of CD44 sensitized BCSCs to the anti-tumor agent doxorubicin. This study aimed to determine if CD44 knockdown caused BCSCs to differentiate into breast cancer non-stem cells (non-BCSCs).MethodsWe isolated a breast cancer cell population (CD44+CD24- cells) from primary cultures of malignant breast tumors. These cells were sorted into four sub-populations based on their expression of CD44 and CD24 surface markers. CD44 knockdown in the BCSC population was achieved using small hairpin RNA lentivirus particles. The differentiated status of CD44 knock-down BCSCs was evaluated on the basis of changes in CD44+CD24- phenotype, tumorigenesis in NOD/SCID mice, and gene expression in relation to renewal status, metastasis, and cell cycle in comparison with BCSCs and non-BCSCs.ResultsKnockdown of CD44 caused BCSCs to differentiate into non-BCSCs with lower tumorigenic potential, and altered the cell cycle and expression profiles of some stem cell-related genes, making them more similar to those seen in non-BCSCs.ConclusionsKnockdown of CD44 is an effective strategy for attacking the stemness of BCSCs, resulting in a loss of stemness and an increase in susceptibility to chemotherapy or radiation. The results of this study highlight a potential new strategy for breast cancer treatment through the targeting of BCSCs.
Highlights
Breast cancer stem cells (BCSCs) are the source of breast tumors
Isolation and culture of BCSCs and non-BCSCs Primary cultures were derived from 10 breast tumor samples, including eight well-developed tumors with many cells expanding from the tissues and two samples that were infected with micro-organisms
The percentages of cells in G1/G0 phase in BCSCs, non-BCSCs and CD44 knockdown BCSCs were similar. These results suggest that CD44 knockdown decreased proliferating ability and extended S phase to increase the similarities with non-BCSCs
Summary
Breast cancer stem cells (BCSCs) are the source of breast tumors. Compared with other cancer cells, cancer stem cells show high resistance to both chemotherapy and radiotherapy. The existence of breast cancer stem cells (BCSCs) in malignant breast tumors has been demonstrated in many previous studies [1,2,3,4] These stem cells exhibit a range of phenotypes, including CD44+CD24-, CD44 +CD24-/dim, CD44+CD24-/dimESA+ and CD44+CD24-Lin[1,2,3,4]. These cells possess specific characteristics, such as approaches for breast cancer treatment, especially in terms of BCSC-targeting therapy. The resistance of BCSCs to radiation and chemotherapy means that there is a need to develop agents able to attack this cell population Because of their stemness, targeting therapies have usually been designed to regulate the self-renewal characteristics, as well as the differentiation of stem cells. Several strategies designed to target BCSCs are currently available, and can be divided into two main groups: those directly targeting BCSCs and those that indirectly targeting BCSCs through the cell microenvironment
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