title: Blocking the formation of radiation-induced breast cancer stem cells.
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 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.
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Wang
authors.forename: Wende
authors.initials: W
authors.lastname: Li
authors.forename: Shalin S
authors.initials: SS
authors.lastname: Patel
authors.forename: Juan
authors.initials: J
authors.lastname: Cong
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Francesco
authors.initials: F
authors.lastname: Sabbatino
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Liu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qi
authors.forename: Peigen
authors.initials: P
authors.lastname: Huang
authors.forename: Hang
authors.initials: H
authors.lastname: Lee
authors.forename: Alphonse
authors.initials: A
authors.lastname: Taghian
authors.forename: Jian-Jian
authors.initials: JJ
authors.lastname: Li
authors.forename: Albert B
authors.initials: AB
authors.lastname: DeLeo
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: Michael W
authors.initials: MW
authors.lastname: Epperly
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.forename: Amy
authors.initials: A
authors.lastname: Ly
authors.forename: Elena F
authors.initials: EF
authors.lastname: Brachtel
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology* / Q000532:radiotherapy* / Q000601:surgery; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D009381:Neoplasms, Radiation-Induced / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000528:radiation effects*; D011836:Radiation Tolerance; D018714:Radiotherapy, Adjuvant; D011897:Random Allocation; D014162:Transfection