Blocking the formation of radiation–induced breast cancer stem cells
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Yangyang Wang1,10, Wende Li2,10, Shalin S. Patel3,10, Juan Cong1,10, Nan Zhang1,10, Francesco Sabbatino1,10, Xiaoyan Liu1, Yuan Qi1, Peigen Huang2,10, Hang Lee4,10, Alphonse Taghian2,10, Jian-Jian Li5, Albert B. DeLeo6, Soldano Ferrone1,3,10, Michael W. Epperly7, Cristina R. Ferrone8,10, Amy Ly9,10, Elena F. Brachtel9,10 and Xinhui Wang1,10
1 Division of Surgical Oncology, Department fo Surgery, Massachusetts General Hospital, Boston, MA
2 Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA
3 Department of Orthopaedics, Massachusetts General Hospital, Boston, MA
4 Department of Biostatistics Center, Massachusetts General Hospital, Boston, MA
5 Department of Radiation Oncology, University of California, Davis, Sacramento, CA
6 Department of Pathology, University of Pittsburgh, Pittsburgh, PA
7 Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA
8 Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA
9 Department of Pathology, Massachusetts General Hospital, Boston, MA
10 Harvard Medical School, Boston, MA
Xinhui Wang, email:
Keywords: Breast Cancer, Radiation, Cancer Stem Cells, NF-kappaB, Stemness genes
Received: February 4, 2014 Accepted: May 18, 2014 Published: May 20, 2014
The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer.
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