STAT1 promotes radioresistance of CD44⁺/CD24^−/low cells in breast cancer

Abstract

Breast cancer-initiating cells are a relatively radioresistant subpopulation of breast cancer cells. However, the mechanism of this radioresistance is still unclear. This study aimed to investigate the effect of radiation on the levels of signal transducer and activator of transcription 1 (STAT1) in mammospheres of cancer-initiating cells and monolayer cultures of MCF-7 cells. We isolated CD44(+)/CD24(-/low) cancer-initiating cells from MCF-7 cells and propagated them as mammospheres. Next we used realtime quantitative reverse-transcriptase polymerase chain reaction to examine the mRNA level of STAT1 in mammospheres of breast cancer-initiating cells and monolayer cultures of MCF-7 cells. The apoptosis rate and surviving fraction using clonogenic assays was observed after treating the cells with a STAT1 inhibitor. After irradiation, the STAT1 level in the mammospheres was higher than that in the monolayer cultures. STAT1 inhibitor treatment did not cause significant changes in the apoptosis rate and surviving fraction in the MCF-7 monolayer cultures. However, the inhibitor treatment caused significant differences in the apoptosis rate and surviving fraction in mammospheres. Our study provides the first evidence that STAT1 signaling contributes to radioresistance in breast cancer-initiating cells and reveals STAT1 as a promising target to reduce radioresistance and enhance the efficacy of radiotherapy for breast cancer.

CD95/Fas Increases Stemness in Cancer Cells by Inducing a STAT1-Dependent Type I Interferon Response

“…In addition, a link between STAT1 and therapy resistance has been uncovered (Khodarev et al, 2004; Khodarev et al, 2007; Rickardson et al, 2005; Weichselbaum et al, 2008). Interestingly, one report demonstrated that STAT1 signaling contributes to radioresistance in breast cancer-initiating cells (Zhan et al, 2011). …”

Molecular Pathways: Interferon/Stat1 Pathway: Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth

“…Consistent with these results, suppression of STAT1 by fludarabine led to the radiosensitization of renal cell carcinoma cell lines (21). Zhan and colleagues showed that increased expression of STAT1 promotes radioresistance of breast cancer stem-like cells cultured as mammospheres (22). Frykn€ as and colleagues showed that a myeloma cell line overexpressing STAT1 and ISGs was significantly more radioresistant relative to the parental cell line exhibiting a low expression of STAT1 (23).…”

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

“…In fact, the ability of these cells to replicate in an in vitro model following at least four generations of xenograft transplanted mice has also suggested their significant role in tumor relapse and metastasis (23). Potential mechanisms of chemotherapy and radiation resistance associated with this phenotype were shown to include the presence of lower concentration of reactive oxygen species, cell dormancy, efficient DNA-repair mechanisms, overexpression of EMT markers, and activation of WNT/β-catenin, Hedgehog and NOTCH signaling pathways and signal transducer and activator of transcription 1 (STAT1) and STAT3 signaling (5,24,(25)(26)(27)(28)(29)(30). As a consequence, the CD44 + /CD24 −/low phenotype in breast cancer is currently being assessed as a therapeutic target.…”