USP30-AS1 Dictates Breast Cancer Cell Fate and Chemoresistance via a miR-3646/FZD7/Wnt/β-Catenin Circuit

Cancer stem cells (CSCs) play a pivotal role in promoting tumorigenesis, drug resistance, invasion, and metastasis. Recent studies indicate that long non-coding RNAs (LncRNAs) directly or indirectly regulate CSCs, influencing tumor progression. This study investigated the role of LncRNA USP30-AS1 in maintaining stemness and chemoresistance in breast cancer. USP30-AS1 was significantly upregulated in BCSC-enriched mammospheres derived from MDA-MB-231 and MCF-7 cell lines, where it correlated with elevated stemness markers (CD44, ALDH1A1, OCT4) and an increased proportion of ALDH+ cells. Functional experiments demonstrated that knockdown of USP30-AS1 reduced spheroid formation, stemness marker expression, chemoresistance, migration, and invasion, while its overexpression promoted these phenotypes. Mechanistically, USP30-AS1 acts as a competing endogenous RNA (ceRNA) by sponging miR-3646, which leads to the derepression of Frizzled-7 (FZD7) and subsequent activation of the Wnt/β-catenin signaling pathway. These findings identify USP30-AS1 as a critical promoter of stemness, chemoresistance, and metastasis in BCSCs via the miR-3646/FZD7/Wnt axis, suggesting it is a potential therapeutic target for breast cancer intervention.