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. Herewe identified that Frizzled 2 (Fzd2), one member of Wnt receptor Frizzled family, induced humanbreast cancer (BC) cell stemness via non-canonical Wnt pathways. Fzd2 was overexpressed inhuman BC tissues, and Fzd2 overexpression was associated with an unfavorable outcome. Fzd2knockdown (KD) disturbed the mesenchymal-like phenotype, migration and invasion of BC cells.Moreover, Fzd2 KD impaired BC cell mammosphere formation, reduced Lgr5+ BC cellsubpopulation, and enhanced sensitivity of BC cells to chemical agents. Mechanistically, Fzd2modulated and bound with Wnt5a/b and Wnt3 to activate several oncogenic pathways such as IL-6/Stat3, Yap1 and TGF-beta1/Smad3. These data indicate that Fzd2 contributes to BC cellmesenchymal-like stemness; targeting Fzd2 may inhibit BC recurrence, metastasis andchemoresistance.