title: High aldehyde dehydrogenase activity enhances stem cell features in breast cancer cells by activating hypoxia-inducible factor-2α.
abstract: High aldehyde dehydrogenase (ALDH) activity has been recognized as a marker of cancer stem cells (CSCs) in breast cancer. In this study, we examined whether inhibition of ALDH activity suppresses stem-like cell properties in a 4T1 syngeneic mouse model of breast cancer. We found that ALDH-positive 4T1 cells showed stem cell-like properties in vitro and in vivo. Blockade of ALDH activity reduced the growth of CSCs in breast cancer cell lines. Treatment of mice with the ALDH inhibitor diethylaminobenzaldehyde (DEAB) significantly suppressed 4T1 cell metastasis to the lung. Recent evidence suggests that ALDH affects the response of stem cells to hypoxia; therefore, we examined a possible link between ALDH and hypoxia signaling in breast cancer. Hypoxia-inducible factor-2α (HIF-2α) was highly dysregulated in ALDH-positive 4T1 cells. We observed that ALDH was highly correlated with the HIF-2α expression in breast cancer cell lines and tissues. DEAB treatment of breast cancer cells reduced the expression of HIF-2α in vitro. In addition, reduction of HIF-2α expression suppressed in vitro self-renewal ability and in vivo tumor initiation in ALDH-positive 4T1 cells. Therefore, our findings may provide the evidence necessary for exploring a new strategy in the treatment of breast cancer.
authors.affiliation: Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
authors.forename: Ran-Ju
authors.initials: RJ
authors.lastname: Kim
authors.forename: Jeong-Ran
authors.initials: JR
authors.lastname: Park
authors.forename: Kyung-Jin
authors.initials: KJ
authors.lastname: Roh
authors.forename: A-Ram
authors.initials: AR
authors.lastname: Choi
authors.forename: Soo-Rim
authors.initials: SR
authors.lastname: Kim
authors.forename: Pyeung-Hyeun
authors.initials: PH
authors.lastname: Kim
authors.forename: Jong Han
authors.initials: JH
authors.lastname: Yu
authors.forename: Jong Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Sei-Hyun
authors.initials: SH
authors.lastname: Ahn
authors.forename: Gyungyub
authors.initials: G
authors.lastname: Gong
authors.forename: Jae-Woong
authors.initials: JW
authors.lastname: Hwang
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Kang
authors.forename: Gu
authors.initials: G
authors.lastname: Kong
authors.forename: Yhun Yhong
authors.initials: YY
authors.lastname: Sheen
authors.forename: Jeong-Seok
authors.initials: JS
authors.lastname: Nam
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000502:physiology*; D050814:Octamer Transcription Factor-3 / Q000502:physiology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000444:Aldehyde Dehydrogenase; D051792:Basic Helix-Loop-Helix Proteins; D050814:Octamer Transcription Factor-3; D000099162:Endothelial PAS Domain-Containing Protein 1; C494173:POU5F1 protein, human