Abstract
Chemotherapy currently remains the standard treatment for triple-negative breast cancer (TNBC). However, TNBC frequently develop chemoresistance, which is responsible for cancer recurrence and distal metastasis. Both DNA damage repair and stemness are related to chemoresistance. FZD5, a member in Frizzled family, was identified to be preferentially expressed in TNBC, and associated with unfavorable prognosis. Loss and gain of function studies revealed that FZD5 contributed to TNBC cell G1/S transition, DNA replication, DNA damage repair, survival, and stemness. Mechanistically, transcription factor FOXM1, which promoted BRCA1 and BIRC5 transcription, acted as a downstream effecter of FZD5 signaling. FOXM1 overexpression in FZD5-deficient/low TNBC cells induced FZD5-associated phenotype. Finally, Wnt7B, a specific ligand for FZD5, was shown to be involved in cell proliferation, DNA damage repair, and stemness. Taken together, FZD5 is a novel target for the development of therapeutic strategies to overcome chemoresistance and prevent recurrence in TNBC.
Highlights
Breast cancer is the most common malignant tumor in women
The Cancer Genome Atlas (TCGA) database was interrogated for Frizzled 5 (FZD5) mRNA expression in breast cancer tissues
Higher FZD5 expression was correlated with shorter overall survival (OS), recurrence-free survival (RFS), distal metastasis-free survival (DMFS), and post-progression survival (PPS) (Fig. 1C)
Summary
Breast cancer is the most common malignant tumor in women. Detection and systemic therapies have decreased the mortality in North America and the European Union[1]. Triple-negative breast cancer (TNBC) currently lack established molecular targets, and TNBC patients usually have an unfavorable prognosis. Cytotoxic chemotherapy remains the standard treatment for TNBC2. TNBC generally have a high response rate to chemotherapy, they frequently develop chemoresistance[3]. It is crucial to identify new molecular targets and develop novel strategies by elucidating the mechanisms of chemoresistance
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