Targeting Breast Cancer Stem Cells Using Naturally Occurring Phytoestrogens

Breast cancer therapies have made significant strides in improving survival for patients over the past decades. However, recurrence and drug resistance continue to challenge long-term recurrence-free and overall survival rates. Mounting evidence supports the cancer stem cell model in which the existence of a small population of breast cancer stem cells (BCSCs) within the tumor enables these cells to evade conventional therapies and repopulate the tumor, giving rise to more aggressive, recurrent tumors. Thus, successful breast cancer therapy would need to target these BCSCs, as well the tumor bulk cells. Since the Women's Health Initiative study reported an increased risk of breast cancer with the use of conventional hormone replacement therapy in postmenopausal women, many have turned their attention to phytoestrogens as a natural alternative. Phytoestrogens are plant compounds that share structural similarities with human estrogens and can bind to the estrogen receptors to alter the endocrine responses. Recent studies have found that phytoestrogens can also target BCSCs and have the potential to complement conventional therapy eradicating BCSCs. This review summarized the latest findings of different phytoestrogens and their effect on BCSCs, along with their mechanisms of action, including selective estrogen receptor binding and inhibition of molecular pathways used by BCSCs. The latest results of phytoestrogens in clinical trials are also discussed to further evaluate the use of phytoestrogen in the treatment and prevention of breast cancer.