Multiple molecular targets in breast cancer therapy by betulinic acid

Breast cancer is the second most common type of cancer in the world, and is by far the most prevalent form of cancer in women. However, the efficacy of current treatments for breast cancer is limited. In addition to the high risk of recurrence, some of these have side effects that significantly reduce the quality of life. Therefore, new avenues of treatment for breast cancer are needed. Betulinic acid (BA), a pipeline anticancer drug, exerts anti-proliferative effects on breast cancer cells is mainly through inhibition of cyclin and topoisomerase expression, leading to cell cycle arrest. It induces apoptosis through mitochondrial pathway and anti-angiogenesis effect by inhibiting the expression of transcription factor nuclear factor kappa B (NF-κB), specificity protein (Sp) transcription factors, and vascular endothelial growth factor (VEGF) signaling. In addition, it exerts anti-metastatic effect by inhibiting the expression of matrix metalloproteases. The specific targets of BA in breast cancer are reported to be the estrogen receptor and various multidrug resistance proteins. Synergistically interactions of BA with other chemotherapeutics are also described in the literature. In this review, we describe the detailed published mechanisms of action of BA, a pentacyclic triterpene with a lupine skeleton, on multiple molecular targets to treat breast cancer. We hope that this review will provide basic information in support of future studies of effects of BA on breast cancer cells.