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Abstract
Emerging evidence suggests that the mammalian target of rapamcyin (mTOR) pathway is associated with radio-resistance in cancer treatment. We hypothesised that phosphorylated ribosomal S6 kinase 1 (p-S6K1), a major downstream regulator of the mTOR pathway, may play a role in predicting radio-resistance. Therefore, we evaluated the association of p-S6K1 expression with radio-resistance in breast cancer cell lines and patients. During median follow-up of 33 (range, 0.1-111) months for 1770 primary breast cancer patients who underwent surgery, patients expressing p-S6K1 showed worse 10-year loco-regional recurrence-free survival (LRFS) compared to that of p-S6K1-negative patients after radiotherapy (93.4% vs. 97.7%, p = 0.015). Multivariate analysis revealed p-S6K1 expression as a predictor of radio-resistance (hazard ratio 7.9, 95% confidence interval 1.1-58.5, p = 0.04). In vitro, CD44high/CD24low MCF7 cells with a radioresistant phenotype expressed higher levels of p-S6K1 than control MCF7 cells. Furthermore, the combination of radiation with treatment of everolimus, an mTOR-S6K1 pathway inhibitor, sensitised CD44high/CD24low MCF7 cells to a greater extent than MCF7 cells. This study provides in vivo and in vitro evidence for p-S6K1 expression status as an important marker for predicting the resistance to radiotherapy and as a possible target for radio-sensitization in breast cancer patients.

Author information

Choi J1,2, Yoon YN3,4, Kim N1, Park CS1, Seol H5, Park IC6, Kim HA1, Noh WC1, Kim JS7,8, Seong MK9.
1
Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
2
Department of Surgery, National Medical Centre, Seoul, Korea.
3
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
4
Radiological and Medico-Oncological Sciences, University of Science and Technology, Daejeon, Korea.
5
Department of Pathology, Korea Cancer Centre Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
6
Division of Basic Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
7
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea. jaesung@kirams.re.kr.
8
Radiological and Medico-Oncological Sciences, University of Science and Technology, Daejeon, Korea. jaesung@kirams.re.kr.
9
Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea. mklegend@kcch.re.kr.