FZD7 expression marks mammary tumor-initiating cells

The WNT signaling pathway has long been implicated in tumorigenesis across multiple cancer types, including breast cancer. However, the complexity arising from the large number of WNTs and their receptors has made it challenging to pinpoint specific components driving tumor development. Using the MMTV-Wnt1 genetically engineered mouse model, which develops mixed-lineage mammary tumors resembling triple-negative breast cancer and composed of both basal and luminal subtypes, we identify the frizzled class receptor 7 (Fzd7) as a key player. Fzd7 is expressed on mammary tumor cells that show enhanced tumorigenic potential in both orthotopic transplantation and tumor organoid assays. Despite the cellular heterogeneity of MMTV-Wnt1 tumors, treatment with a Fzd7-specific antibody-drug conjugate significantly suppresses tumor growth, suggesting that Fzd7-expressing cells are critical drivers of tumor progression. These findings show that Fzd7 marks a population of putative tumor-initiating cells and that targeting Fzd7 offers a promising therapeutic strategy for breast cancer.