Fzd2 Contributes to Breast Cancer Cell Mesenchymal-Like Stemness and Drug Resistance

Cancer cell stemness is responsible for cancer relapse, distal metastasis, and drug resistance. Here we identified that Frizzled 2 (Fzd2), one member of Wnt receptor Frizzled family, induced human breast cancer (BC) cell stemness via noncanonical Wnt pathways. Fzd2 was overexpressed in human BC tissues, and Fzd2 overexpression was associated with an unfavorable outcome. Fzd2 knockdown (KD) disturbed the mesenchymal-like phenotype, migration, and invasion of BC cells. Moreover, Fzd2 KD impaired BC cell mammosphere formation, reduced Lgr5(+) BC cell subpopulation, and enhanced sensitivity of BC cells to chemical agents. Mechanistically, Fzd2 modulated and bound with Wnt5a/b and Wnt3 to activate several oncogenic pathways such as interleukin-6 (IL-6)/Stat3, Yes-associated protein 1 (Yap1), and transforming growth factor-β1 (TGF-β1)/Smad3. These data indicate that Fzd2 contributes to BC cell mesenchymal-like stemness; targeting Fzd2 may inhibit BC recurrence, metastasis, and chemoresistance.