title: Caveolin-1 mediates chemoresistance in breast cancer stem cells via β-catenin/ABCG2 signaling pathway.
abstract: Accumulating evidence has suggested that cancer stem cells (CSCs) are at the root of drug resistance, and recent studies have indicated that caveolin-1, a membrane transporter protein, is involved in the regulation of cancer chemoresistance and stem cell signaling. However, the current understanding of the role of caveolin-1 in breast cancer development remains controversial. Herein, we demonstrate that caveolin-1 expression was upregulated after breast cancer chemotherapy in vitro and in vivo, accompanied by co-overexpression of β-catenin and ATP-binding cassette subfamily G member 2 (ABCG2) signaling. Additionally, breast CSCs were enriched for caveolin-1 expression. Caveolin-1 silencing sensitized breast CSCs by limiting their self-renewal ability but promoting the differentiation process. β-catenin silencing prevented the enhanced chemoresistance of CSCs induced by caveolin-1 overexpression, indicating that β-catenin is an essential molecule responsible for caveolin-1-mediated action. Further mechanistic investigation revealed that caveolin-1 silencing could downregulate the β-catenin/ABCG2 pathway through glycogen synthase kinase 3 beta activation and Akt inhibition, resulting in increased β-catenin phosphorylation and proteasomal degradation. Clinical investigation also revealed a close correlation between caveolin-1 and β-catenin/ABCG2 signaling in breast cancer samples. Notably, caveolin-1 was highly elevated in triple-negative breast cancer, and caveolin-1 silencing significantly impaired the tumorigenicity and chemoresistance of breast CSCs in in vivo models. Overall, our study not only highlights the role of caveolin-1 in mediating the chemoresistance of breast CSCs via β-catenin/ABCG2 regulation but also provides novel approaches for future therapies targeting CSCs.
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou 510120, China, School of Chinese Medicine, University of Hong Kong, Pokfulam, Hong Kong, China and.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Chinese Medicine, University of Hong Kong, Pokfulam, Hong Kong, China and.
authors.forename: Neng
authors.initials: N
authors.lastname: Wang
authors.affiliation: Guangdong Women and Child Health Hospital, Guangzhou 510120, China.
authors.forename: Wenping
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
authors.forename: Pengxi
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
authors.forename: Qianjun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
authors.forename: Honglin
authors.initials: H
authors.lastname: Situ
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
authors.forename: Shaowen
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
authors.forename: Li
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: School of Chinese Medicine, University of Hong Kong, Pokfulam, Hong Kong, China and.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Shen
authors.affiliation: School of Chinese Medicine, University of Hong Kong, Pokfulam, Hong Kong, China and jpjpchen@yahoo.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Chen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D006801:Humans; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; C495540:CAV1 protein, human; D051242:Caveolin 1; D009363:Neoplasm Proteins; D051176:beta Catenin