Kaempferol Improves Breast Cancer-Related Depression through the COX-2/PGE2 Pathway

Breast cancer-related depression (BCRD) is strongly associated with BC and increases recurrence and mortality. This study investigated the role of kaempferol in the pathogenesis of BCRD and its underlying mechanism.

4T1 mouse BC cells were treated with corticosterone (Cort) in vitro to develop a neuronal injury model, and a BCRD mouse model was established by injecting 4T1 cells and Cort. The effects of kaempferol on 4T1 cells and BCRD models were measured by behavioral tests, Cell Counting Kit-8 assay, wound healing assay, colony formation assay, Western blot analysis, quantitative real-time PCR, hematoxylin and eosin staining, enzyme-linked immunosorbent assay, and immunofluorescence. BCRD cells were transfected with the cyclo-oxygenase-2 (COX-2) overexpression plasmid to study the role of the COX-2/prostaglandin E2 (PGE2) axis in the anti-BCRD activity of kaempferol. The connection between kaempferol and COX-2 was analyzed by molecular docking.

Kaempferol reduced the viability, migration, and clones of 4T1 cells and inhibited BC growth and depression-like behavior in mice. Kaempferol alleviated inflammation in BCRD, decreased interleukin 1 beta (IL-1β) and IL-6 levels, and increased transforming growth factor beta 1 (TGF-β1) and IL-10 levels. In addition, kaempferol elevated the levels of serotonin, dopamine, and norepinephrine and the amount of 5-Bromo-2'-deoxyuridine/neuronal nuclei-positive cells. Kaempferol downregulated COX-2 and PGE2, and kaempferol could dock with the protein structure of COX-2. Overexpression of COX-2 reduced BCRD viability, upregulated IL-1β and IL-6 levels, and downregulated TGF-β1 and IL-10 expression. Overexpression of COX-2 reversed the protective effects of kaempferol.

Kaempferol exerted anti-BCRD effects, at least in part by inhibiting the COX-2/PGE2 pathway, which regulates neuroinflammation, neurotransmitter imbalance, and defective neurogenesis. Therefore, kaempferol may be a promising candidate active ingredient for treating BCRD.