Dark Sweet Cherry Anthocyanins Suppressed Triple-Negative Breast Cancer Pulmonary Metastasis and Downregulated Genes Associated with Metastasis and Therapy Resistance

Dark sweet cherries (DSC) phytochemicals have emerged as a promising dietary strategy to combat triple-negative breast cancer (TNBC). This study explored the effects of DSC extract rich in anthocyanins (ACN) as a chemopreventive agent and as a complement to doxorubicin (DOX) in treating TNBC tumors and metastasis using a 4T1 syngeneic animal model. Initiating ACN intake as a chemopreventive one week before 4T1 cell implantation significantly delayed tumor growth without any signs of toxicity. Both DOX treatment and the combination of DOX-ACN effectively delayed tumor growth rate, but DOX-ACN allowed for body weight gain, which was hindered by DOX alone. As a chemopreventive, ACN downregulated metastasis- and immune-suppression-related genes, including STAT3, Snail1, mTOR, SIRT1, TGFβ1, IKKβ, and those unaffected by DOX alone, such as HIF, Cd44, and Rgcc32. Correlations between mRNA levels seen in control and DOX groups were absent in ACN and/or DOX-ACN groups, indicating that Cd44, mTOR, Rgcc32, SIRT1, Snail1, and TGFβ1 may be ACN targets. The DOX-ACN treatment showed a trend toward enhanced efficacy involving CREB, PI3K, Akt-1, and Vim compared to DOX alone. Particularly, ACN significantly suppressed lung metastasis compared to the other groups. ACN also decreased the frequency and incidence of metastasis in the liver, heart, kidneys, and spleen, while their metastatic area (%) and number of breast cancer (BC) metastatic tumor nodules were lowered without reaching significance. Further research is needed to explore the efficacy of combining ACN with drug therapy in the context of drug resistance.