Blocking the formation of radiation-induced breast cancer stem cells

Yangyang Wang, Wende Li, Shalin S. Patel, Juan Cong, Nan Zhang, Francesco Sabbatino, Xiaoyan Liu, Yuan Qi, Peigen Huang, Hang Lee, Alphonse Taghian, Jian-Jian Li, Albert B. DeLeo, Soldano Ferrone, Michael W. Epperly, Cristina R. Ferrone, Amy Ly, Elena F. Brachtel, Xinhui Wang

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

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 radiation (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.

Original languageEnglish (US)
Pages (from-to)3743-3755
Number of pages13
JournalOncotarget
Volume5
Issue number11
StatePublished - 2014

Keywords

  • Breast cancer
  • Cancer stem cells
  • NF-kappaB
  • Radiation

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Wang, Y., Li, W., Patel, S. S., Cong, J., Zhang, N., Sabbatino, F., Liu, X., Qi, Y., Huang, P., Lee, H., Taghian, A., Li, J-J., DeLeo, A. B., Ferrone, S., Epperly, M. W., Ferrone, C. R., Ly, A., Brachtel, E. F., & Wang, X. (2014). Blocking the formation of radiation-induced breast cancer stem cells. Oncotarget, 5(11), 3743-3755.