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.