Abstract
AimsAlthough a relatively small proportion of all breast cancer (BC), triple negative (TN) BC is responsible for a relatively large proportion of BC deaths because of its worse clinical outcome. To investigate whether a carbon ion beam alone or in combination with cisplatin (CDDP) has a beneficial effect compared to X-rays, we target triple negative (TN) breast cancer stem-like cells (CSCs).MethodsHuman breast CSCs sorted from MDA-MB-231 and MDA-MB-453 cells were treated with a carbon ion beam or X-ray irradiation alone or in combination with CDDP, and then colony, spheroid and tumor formation assays, RT-PCR Array analysis, and immunofluorescence γH2AX foci assay were performed.ResultsThe colony, spheroid formation, and tumorigenicity assays confirmed that CD44+/CD24- and ESA+/CD24- cells have CSC properties in MDA-MB-231 and MDA-MB-453 cells, respectively. The proportion of CSCs was more enriched after CDDP combination with either X-ray or carbon ion beam, however carbon ion beam combined with CDDP significantly suppressed colony and spheroid formation and more significantly inhibited cell cycle progression (sub-G1 arrest) compared to X-ray combined with CDDP or carbon ion beam alone. RT-PCR Array analysis showed that carbon ion beam combined with CDDP significantly induced apoptosis-related Cytochrome c, almost completely eliminated expression of the CSC markers CD44 and ESA, and significantly inhibited angiogenesis, and metastasis-related HIF1α and CD26 compared to carbon ion beam alone, X-ray alone, or X-ray combined with CDDP. The immunofluorescence assay showed that not only the number but also the size of γH2AX foci in CSCs were larger 24 h after carbon ion beam combined with CDDP compared to those of X-ray alone and X-ray combined with CDDP.ConclusionsCarbon ion beam combined with CDDP has superior potential to kill TN breast CSCs with irreparable severe DNA damage and enhanced apoptosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0429-7) contains supplementary material, which is available to authorized users.
Highlights
Human breast cancer (BC) has become one of the leading causes of cancer-related death for women worldwide, and it is rapidly increasing in Asian countries including Japan [1,2,3]
The proportion of ESA+/CD24- cells in MDA-MB-453 cells significantly decreased at 96 h after carbon ion beam alone and surprisingly by X-ray irradiation alone, but significantly increased by X-ray combined with CDDP or CDDP alone
We found that after treatment with carbon ion beam in combination with CDDP for radioresistant Cancer stem-like cell (CSC) delivered from MDA-MB-231 cells, apoptosis-related gene expressions like Cytochrome c and autophagy-related genes like LC3 showed significant enhancement or a strong tendency to increase compared to that of carbon ion beam, X-ray and CDDP alone or X-ray combined with CDDP suggesting that carbon ion beam combined with CDDP may have more power to induce multiple cell death (Fig. 4a, b)
Summary
Human breast cancer (BC) has become one of the leading causes of cancer-related death for women worldwide, and it is rapidly increasing in Asian countries including Japan [1,2,3]. Triple-negative breast cancers (TNBC), defined as tumors that are negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), nowadays represent the focus of increasing interest at the clinical, biological and epidemiological level [6,7,8], due to the aggressive behavior of the tumor, poor prognosis and present lack of targeted therapies [9,10,11]. The very high rate of heterogeneity in BC cell phenotypes [14], accompanied by the dynamic plasticity of the BC microenvironment [15], make tumor categorization a demanding task, especially in relation to therapeutic responses and risk of disease progression [16]. The development of new potent CSC targeting therapeutics is highly desirable [22,23,24]
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