RRC ID 65860
Author Shiraishi A, Tachi K, Essid N, Tsuboi I, Nagano M, Kato T, Yamashita T, Bando H, Hara H, Ohneda O.
Title Hypoxia promotes the phenotypic change of aldehyde dehydrogenase activity of breast cancer stem cells.
Journal Cancer Sci
Abstract Stable breast cancer cell (BCC) lines are valuable tools for the identification of breast cancer stem cell (BCSC) phenotypes that develop in response to several stimuli as well as for studying the basic mechanisms associated with the initiation and maintenance of BCSCs. However, the characteristics of individual, BCC-derived BCSCs varies and these cells show distinct phenotypes depending on the different BCSC markers used for their isolation. Aldehyde dehydrogenase (ALDH) activity is just such a recognized biomarker of BCSCs with a CD44+ /CD24- phenotype. We isolated BCSCs with high ALDH activity (CD44+ /CD24- /Aldefluorpos ) from a primary culture of human breast cancer tissue and observed that the cells had stem cell properties compared to BCSCs with no ALDH activity (CD44+ /CD24- /Aldefluorneg ). Moreover, we found Aldefluorpos BCSCs had a greater hypoxic response and subsequent induction of HIF-1α expression compared to the Aldefluorneg BCSCs. We also found that knocking down HIF-1α, but not HIF-2α, in Aldefluorpos BCSCs led to a significant reduction of the stem cell properties through a decrease in the mRNA levels of genes associated with the epithelial-mesenchymal transition. Indeed, HIF-1α overexpression in Aldefluorneg BCSCs led to Slug and Snail mRNA increase and the associated repression of E-cadherin and increase in Vimentin. Of note, prolonged hypoxic stimulation promoted the phenotypic changes of Aldefluorneg BCSCs including ALDH activity, tumorigenesis and metastasis, suggesting that hypoxia in the tumor environment may influence BCSC fate and breast cancer clinical outcomes.
Volume 108(3)
Pages 362-372
Published 2017-3-1
DOI 10.1111/cas.13147
PMID 28012234
PMC PMC5378271
MeSH Aged Aldehyde Dehydrogenase / metabolism* Animals Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism Breast Neoplasms / pathology* Cadherins / metabolism Cell Hypoxia / physiology* Cell Proliferation Cell Transformation, Neoplastic / pathology* Epithelial-Mesenchymal Transition / genetics Female Humans Hypoxia-Inducible Factor 1, alpha Subunit / genetics Hypoxia-Inducible Factor 1, alpha Subunit / metabolism Mice Mice, Inbred C57BL Neoplastic Stem Cells / enzymology* Neoplastic Stem Cells / pathology RNA, Messenger / genetics Snail Family Transcription Factors / genetics Spheroids, Cellular / pathology Tumor Cells, Cultured Vimentin / metabolism Xenograft Model Antitumor Assays
IF 4.966
Human and Animal Cells MCF7(RCB1904)