Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that tends to affect young women and has a high propensity to metastasize. No targeted treatments are available for this type of breast cancer due to a lack of estrogen or progesterone receptors or overexpression of human epidermal growth factor receptor type 2 overexpression. Currently, patients have no therapeutic options once standard of care is complete, indicating a need for safe and effective therapies to slow or prevent the progression of TNBC to metastatic disease. Studies showed that isolated polyphenols or polyphenol-rich muscadine grape extracts polyphenols inhibit the proliferation of various cancer cells including breast cancer. A proprietary muscadine grape extract (MGE) was administered to nude mice with human MDA-MB-231 TNBC atumors for 4 weeks to determine the effect of the extract on tumor growth. MGE decreased tumor volume in association with a reduction in the proliferative markers Ki67 and cyclin D1. To determine the molecular mechanisms for the MGE-induced reduction in tumor growth, mouse 4T1, MDA-MB-231, or human BT-549 TNBC cells were treated with MGE, and various signaling pathways were investigated. MGE reduced c-Met, differentially abrogated ERK/MAPK and AKT signaling, and decreased a downstream targets of ERK/MAPK and AKT pathways, cyclin D1. Cyclin D1 reduction was associated with retinoblastoma activation and cell cycle arrest in MDA-MB-231 TNBC cells. MGE-regulated molecular signaling pathways were functionally associated with a dose-dependent reduction in cell proliferation. The pluripotency of MGE and high index of safety and tolerability suggest that the extract may serve as a therapeutic to reduce TNBC progression to metastatic disease.
Keywords: cyclin D1; muscadine grape; polyphenols; proliferation; triple-negative breast cancer.