Chronic oxidative stress causes estrogen-independent aggressive phenotype, and epigenetic inactivation of estrogen receptor alpha in MCF-7 breast cancer cells

Abstract

The role of chronic oxidative stress in the development and aggressive growth of estrogen receptor (ER)-positive breast cancer is well known; however, the mechanistic understanding is not clear. Estrogen-independent growth is one of the features of aggressive subtype of breast cancer. Therefore, the objective of this study was to evaluate the effect of oxidative stress on estrogen sensitivity and expression of nuclear estrogen receptors in ER-positive breast cancer cells. MCF-7 cells chronically exposed to hydrogen peroxide were used as a cell model in this study, and their growth in response to 17-β estradiol was evaluated by cell viability, cell cycle, and cell migration analysis. Results were further confirmed at molecular level by analysis of gene expressions at transcript and protein levels. Histone H3 modifications, expression of epigenetic regulatory genes, and the effect of DNA demethylation were also analyzed. Loss of growth in response to estrogen with a decrease in ERα expression was observed in MCF-7 cells adapted to chronic oxidative stress. Increases in mtTFA and NRF1 in these cells further suggested the role of mitochondria-dependent redox-sensitive growth signaling as an alternative pathway to estrogen-dependent growth. Changes in expression of epigenetic regulatory genes, levels of histone H3 modifications as well as significant restorations of both ERα expression and estrogen response by 5-Aza-2'-deoxycytidine further confirmed the epigenetic basis for estrogen-independent growth in these cells. In conclusion, results of this study suggest that chronic oxidative stress can convert estrogen-dependent nonaggressive breast cancer cells into estrogen-independent aggressive form potentially by epigenetic mechanism.

Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

“…MCF-7 cells chronically exposed to 25 μM H 2 O 2 (simulating oxidative stress in a tumor) showed increased NRF-1 and TFAM expression, decreased ERα expression and increased colony-forming potential (14). E 2 was reported to increase ROS thus activating AKT which phosphorylated and activated NRF-1 (p-NRF-1) and increased transcription of its cell cycle targets: CDC2, PRC1, PCNA, cyclin B1, and CDC25C in MCF-7 cells (15).…”

Computational metabolism modeling predicts risk of distant relapse-free survival in breast cancer patients

“…Now, using flux activities we characterized differences in ROS detoxification and nucleotide interconversion pathways among breast tumor subtypes. Oxidative stress has been related with tumor aggressiveness in ER+ tumors [16]. TNBC tumors also have a high presence of ROS [17].…”

Plasma fluorescent oxidation products and risk of estrogen receptor-negative breast cancer in the Nurses’ Health Study and Nurses’ Health Study II

“…If carotenoids reduce oxidative stress-induced cell damage, we might expect oxidative stress biomarkers to be more strongly associated with ER− breast cancer. Further, chronic exposure to oxidative stress, through hydrogen peroxidate-induced proliferation of intracellular ROS, has been shown to cause loss of ER−alpha expression and conversion of estrogen-dependent breast cancer cells into estrogen-independent phenotype [39], suggesting the importance of oxidative stress on ER− breast cancer risk. However, despite the biological plausibility of positive associations between oxidative stress and ER− breast cancer, we did not observe any significant positive associations in this study.…”