Inhibitors of Keap1-Nrf2 protein-protein interaction reduce estrogen responsive gene expression and oxidative stress in estrogen receptor-positive breast cancer.

Estrogen contributes to the development of breast cancer through estrogen receptor (ER) signaling and by generating genotoxic metabolites that cause oxidative DNA damage. To protect against oxidative stress, cells activate nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream cytoprotective genes that initiate antioxidant responses and detoxify xenobiotics. Nrf2 activation occurs by inhibiting the protein-protein interaction (PPI) between Nrf2 and its inhibitor Keap1, which otherwise targets Nrf2 for ubiquitination and destruction. In this study, we examined a series of novel direct inhibitors of Keap1-Nrf2 PPI in their role in promoting the availability of Nrf2 for antioxidant activity and attenuating estrogen-mediated responses in breast cancer. ER-positive human breast cancer cells MCF-7 were treated with 17ß-estradiol (E2) in the presence or absence of selected Keap1-Nrf2 PPI inhibitors. Keap1-Nrf2 PPI inhibitors suppressed the mRNA and protein levels of estrogen responsive genes induced by E2 exposure, such as PGR. Keap1-Nrf2 PPI inhibitors caused significant activation of Nrf2 target genes. E2 decreased the mRNA and protein level of the Nrf2 target gene NQO1, and the Keap1-Nrf2 PPI inhibitors reversed this effect. The reversal of E2 action by these compounds was not due to binding to ER as ER antagonists. Further, a selected compound attenuated oxidative stress induced by E2, determined by the level of a biomarker 8-oxo-deoxyguanosine. These findings suggest that the Keap1-Nrf2 PPI inhibitors have potent antioxidant activity by activating Nrf2 pathways and inhibit E2-induced gene and protein expression. These compounds may serve as potential chemopreventive agents in estrogen-stimulated breast cancer.

Endocrine-disrupting compounds and metabolomic reprogramming in breast cancer.

Endocrine-disrupting chemicals pose a growing threat to human health through their increasing presence in the environment and their potential interactions with the mammalian endocrine systems. Due to their structural similarity to hormones like estrogen, these chemicals can interfere with endocrine signaling, leading to many deleterious effects. Exposure to estrogenic endocrine-disrupting compounds (EDC) is a suggested risk factor for the development of breast cancer, one of the most frequently diagnosed cancers in women. However, the mechanisms through which EDCs contribute to breast cancer development remain elusive. To rapidly proliferate, cancer cells undertake distinct metabolic programs to utilize existing nutrients in the tumor microenvironment and synthesize macromolecules de novo. EDCs are known to dysregulate cell signaling pathways related to cellular metabolism, which may be an important mechanism through which they exert their cancer-promoting effects. These altered pathways can be studied via metabolomic analysis, a new advancement in -omics technologies that can interrogate molecular pathways that favor cancer development and progression. This review will summarize recent discoveries regarding EDCs and the metabolic reprogramming that they may induce to facilitate the development of breast cancer.

Understanding the Mechanistic Link between Bisphenol A and Cancer Stem Cells: A Cancer Prevention Perspective.

Endocrine disruptors, such as bisphenol A (BPA), have become more frequently present in the environment as contaminants, especially in industrialized countries. Long-term effects of these environmental contaminants in humans are elusive. With their structural similarity to estrogen, many environmental contaminants including BPA, have been shown to mimic the biological functions of estrogen, potentially contributing to the development of breast cancer. It has been well established that BPA exerts estrogenic activity in animal models and in vitro systems. There is a concern for adverse effects from the exposure to BPA in regard to developmental and reproductive toxicities. However, the mechanisms by which BPA promotes breast cancer development remain unknown. Understanding the role of endocrine disruptors and their key mechanisms of action is important for public health, especially by providing a foundation for a better intervention approach in cancer prevention.