Antibody/siRNA Nanocarriers Against Wnt Signaling Suppress Oncogenic and Stem-Like Behavior in Triple-Negative Breast Cancer Cells

Abstract

Triple-negative breast cancer (TNBC) is infamous for its aggressive phenotype and poorer prognosis when compared to other breast cancer subtypes. One factor contributing to this poor prognosis is that TNBC lacks expression of the receptors that available hormonal or molecular-oriented therapies attack. New treatments that exploit biological targets specific to TNBC are desperately needed to improve patient outcomes. One promising target for therapeutic manipulation is the Wnt signaling pathway, which has been associated with many invasive breast cancers, including TNBC. This pathway is activated in TNBC cells when extracellular Wnt ligands bind to overexpressed Frizzled7 (FZD7) transmembrane receptors, leading to downstream activation of intracellular β-catenin proteins. To target and inhibit Wnt signaling in TNBC cells, polymer nanoparticles (NPs) modified with anti-FZD7 antibodies and β-catenin small interfering RNAs (siRNAs) were developed, and their impact on the oncogenic behavior of treated TNBC cells was investigated. When compared to control NPs, the Wnt-targeted NPs induced greater levels of Wnt oncogene suppression. This led to greater inhibition of oncogenic and stem-like properties, including cell proliferation, drug resistance, and spheroid formation capacity. This work demonstrates a promising approach for targeting the Wnt pathway in TNBC to counter the cellular phenotypes that drive disease progression.

Keywords: Frizzled7; RNA interference; antibodies; nanomedicine; oncology; targeted therapy; β‐catenin.