The Anticancer Effect of Kaempferol Through Downregulation of CDKs and PD-L1 in Triple-Negative Breast Cancer Cells

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by poor prognosis, high metastatic potential, and limited targeted therapies. Methods: This study evaluates the anticancer activity of kaempferol in two genetically and ethnically distinct TNBC models: MDA-MB-231 (Caucasian) and MDA-MB-468 (African American) cells, utilizing cell viability, cell proliferation, apoptosis, cell cycle arrest, qPCR, and Abby analysis assays. Results: Kaempferol inhibited TNBC cell viability and proliferation in a dose- and time-dependent manner, in both 2D monolayer and three-dimensional (3D) cell cultures, and induced apoptosis and S phase cycle arrest. This investigation demonstrated that kaempferol affects cancer cells by inhibiting CDK1, CDK4, CDK6, and CDK7 at both the gene and protein levels in MDA-MB-231 cells, and specifically CDK6 and CDK7 in MDA-MB-468 cells. It reduced expression of PD-L1, JAK1, STAT3, MUC-1, and NF-κB1 (p50), indicating that the underlying pathway of PD-L1 inhibition may involve targeting the JAK1/STAT3 pathway and downregulating MUC-1, while inhibiting NF-κB1 levels. Kaempferol also inhibited the overexpression of CCL2 and TGM2, which are responsible for the development of resistance to targeted therapies, such as anti-PD-L1 immunotherapy, in TNBC. Conclusion: Kaempferol acts as a multi-target modulator of CDKs and PD-L1-associated signaling in TNBC, extending prior reports of its antiproliferative and pro-apoptotic effects in MDA-MB-231 and, significantly, providing comparative evidence across MDA-MB-231 versus MDA-MB-468 models. Since the levels of PD-L1 have been previously shown to be regulated by CDKs, this study is the first to report the dual inhibitory effect of a flavonoid of natural origin on CDKs and PD-L1 levels in TNBC cells.