FZD7 expression marks mammary tumor–initiating cells

TL;DR

This study identifies FZD7 as a marker for tumor-initiating cells in triple-negative breast cancer and shows its potential as a target for antibody-drug conjugate therapy.

Contribution

The study introduces FZD7 as a novel therapeutic target for triple-negative breast cancer through its role in tumor-initiating cells.

Findings

FZD7 marks tumor-initiating basal cells in the MMTV-Wnt1 mouse model of TNBC.

A FZD7-specific antibody-drug conjugate significantly suppresses tumor growth in mice.

Human TNBC cells show clinical promise for FZD7-targeted therapy.

Abstract

Triple negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options. We identify FZD7 as a key marker of tumor-initiating basal cells in the MMTV-Wnt1 mouse model of TNBC and demonstrate its value as a therapeutic target. Using humanized Fzd7 mice, we show that a highly specific FZD7 antibody enables isolation of FZD7+ tumor cells with enhanced growth potential and selective sensitivity to a FZD7-antibody drug conjugate (ADC). Tumor-derived 3D organoids recapitulate in vivo complexity and provide a platform to evaluate FZD7-dependent growth and drug response. Translation of these findings to human TNBC cells underscores the clinical promise of FZD7-targeted ADC therapy, offering a potential approach for aggressive breast cancers lacking effective treatments.

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.

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