title: Doxycycline inhibits the cancer stem cell phenotype and epithelial-to-mesenchymal transition in breast cancer.
abstract: Experimental evidence suggest that breast tumors originate from breast cancer stem cells (BCSCs), and that mitochondrial biogenesis is essential for the anchorage-independent clonal expansion and survival of CSCs, thus rendering mitochondria a significant target for novel treatment approaches. One of the recognized side effects of the FDA-approved drug, doxycycline is the inhibition of mitochondrial biogenesis. Here we investigate the mechanism by which doxycycline exerts its inhibitory effects on the properties of breast cancer cells and BCSCs, such as mammosphere forming efficiency, invasion, migration, apoptosis, the expression of stem cell markers and epithelial-to-mesenchymal transition (EMT) related markers of breast cancer cells. In addition, we explored whether autophagy plays a role in the inhibitory effect of doxycycline on breast cancer cells. We find that doxycyline can inhibit the viability and proliferation of breast cancer cells and BCSCs, decrease mammosphere forming efficiency, migration and invasion, and EMT of breast cancer cells. Expression of stem cell factors Oct4, Sox2, Nanog and CD44 were also significantly downregulated after doxycycline treatment. Moreover, doxycycline could down-regulate the expression of the autophagy marker LC-3BI and LC-3BII, suggesting that inhibiting autophagy may be responsible in part for the observed effects on proliferation, EMT and stem cell markers. The potent inhibition of EMT and cancer stem-like characteristics in breast cancer cells by doxycycline treatment suggests that this drug can be repurposed as an anti-cancer drug in the treatment of breast cancer patients in the clinic.
authors.affiliation: a Department of Oncology , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , P.R. China.|b Department of Radiation Oncology , David Geffen School of Medicine at UCLA , Los Angeles , CA , USA.
authors.forename: Le
authors.initials: L
authors.lastname: Zhang
authors.affiliation: a Department of Oncology , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , P.R. China.|c Department of Prevention and Cure Center of Breast Disease , Third Hospital of Nanchang , Nanchang , P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: a Department of Oncology , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , P.R. China.
authors.forename: Fengchun
authors.initials: F
authors.lastname: Zhang
authors.affiliation: b Department of Radiation Oncology , David Geffen School of Medicine at UCLA , Los Angeles , CA , USA.|d Jonsson Comprehensive Cancer Center at UCLA , Los Angeles , CA , USA.
authors.forename: Erina
authors.initials: E
authors.lastname: Vlashi
mesh_terms: D001343:Autophagy / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D004318:Doxycycline
keywords: autophagy; breast cancer; cancer stem cells; doxycycline; epithelial-to-mesenchymal transition; mitochondria