Environmental Lead Promotes Breast Cancer Migration and Invasion via the AKR1C3–NF-κB–MMP Axis

<b>Background/Objectives:</b> Environmental exposure to heavy metals is an established risk factor for breast cancer development; however, the molecular mechanisms underlying the contribution of lead (Pb) to disease progression remain unclear. This study aimed to investigate the effects of Pb exposure on breast cancer cells and to delineate the associated mechanisms. <b>Methods:</b> We examined Pb-induced migration and invasion of breast cancer cells using wound-healing and Transwell assays; assessed cell proliferation by flow cytometry and MTT assay; identified potential target genes via RNA sequencing; and further elucidated the underlying mechanisms using integrated molecular biology approaches (including immunofluorescence, Western blotting, and ELISA), functional cellular assays, and bioinformatics analysis. <b>Results:</b> Pb exposure significantly enhanced the migratory and invasive capabilities of breast cancer cells by upregulating aldo-keto reductase family 1 member C3 (AKR1C3), without markedly affecting cell proliferation. Mechanistically, AKR1C3 promoted migration and invasion through activation of NF-κB signaling, leading to upregulated expression of MMP-2 and MMP-9. <b>Conclusions:</b> This study reveals a novel molecular axis-Pb exposure promotes breast cancer cell migration and invasion via the AKR1C3-NF-κB-MMP-2/MMP-9 pathway-and identifies AKR1C3 as a potential therapeutic target for breast cancer associated with environmental heavy metal exposure.