title: WNT pathway inhibitor pyrvinium pamoate inhibits the self-renewal and metastasis of breast cancer stem cells.
abstract: Acquisition of chemoresistance and metastatic phenotype are the major causes of breast cancer treatment failure and cancer-related mortality. Recently, a plethora of experimental and clinical studies points toward a central role of cancer stem cells (CSCs) in the chemoresistance and metastasis. In the present study, we demonstrated that pyrvinium pamoate (PP), an anthelmintic drug, inhibited proliferation of different subtypes of breast cancer cells (luminal: MCF-7, claudin-low: MDA-MB‑231, basal-like: MDA-MB‑468 and Her-2 enriched: SkBr-3) as a novel WNT pathway inhibitor. Additionally, PP was also shown to inhibit self-renewal of breast cancer stem cells (BCSCs) and decrease both CD44+CD24-/low and ALDH-positive BCSCs content in a panel of breast cancer cell lines. Besides, the metastatic potential and expression of EMT markers (such as N-cadherin, vimentin, Snail) were also found suppressed by PP. By using a xenograft model, we next tested the efficacy of PP on tumorigenicity of MDA-MB‑231, one of the most aggressive breast cancer cell lines, and we observed PP significantly delayed tumor growth in vivo. Moreover, in-depth analysis revealed that PP caused inhibition of WNT pathway activity and stemness regulator expression including NANOG, SOX2 and OCT4, which were inherently upregulated in the BCSCs as compared with the bulk of cells within the tumor. Collectively, our findings provide direct evidence for PP serving as a promising high-yield agent targeting BCSCs and cancer heterogeneity. Therefore, strategies combining PP with standard chemotherapy drugs which fail to eliminate the BCSCs hold promise to overcome BCSCs associated treatment resistance and achieve a better therapeutic outcome.
authors.affiliation: Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Le
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Chun
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Shujing
authors.initials: S
authors.lastname: Liang
authors.affiliation: Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Fei
authors.affiliation: Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Yan
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & SJTUSM, Shanghai 200031, P.R. China.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Fengchun
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001943:Breast Neoplasms / Q000378:metabolism*; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology*; D016133:Polymerase Chain Reaction; D011774:Pyrvinium Compounds / Q000737:chemistry*; D060449:Wnt Signaling Pathway
chemical_list: D000970:Antineoplastic Agents; D051927:CD24 Antigen; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D011774:Pyrvinium Compounds; C024631:pyrvinium