Urolithin A: A promising selective estrogen receptor modulator and 27-hydroxycholesterol attenuator in breast cancer.

Abstract

27-hydroxycholesterol (27-HC) is an oxysterol that acts as an endogenous selective estrogen receptor modulator (SERM), and its adverse effects on breast cancer via the estrogen receptor (ER) have provided new insights into the pathology of cholesterol-linked breast cancer. Our earlier in vitro experiments showed that the methanolic extract of pomegranate could exhibit SERM properties and compete with 27-HC. The major constituents of pomegranate are ellagitannins and ellagic acid, which are converted into urolithins by the colonic microbiota. In recent years, urolithins, especially urolithin A (UA) and urolithin B (UB), have been reported to have a plethora of advantageous effects, including antiproliferative and estrogenic activities. In this study, we attempted to determine the potential of urolithins in antagonizing and counteracting the adverse effects of 27-HC in breast cancer cells. Our findings suggested that UA had an antiproliferative capacity and attenuated the proliferative effects of 27-HC, resulting in subsequent loss of membrane potential and apoptosis in breast cancer cells. Further, UA induced estrogen response element (ERE) transcriptional activity and modulated estrogen-responsive genes, exhibiting a SERM-like response concerning receptor binding. Our in vivo hollow fiber assay results showed a loss of cell viability in breast cancer cells upon UA consumption, as well as a reduction in 27-HC-induced proliferative activity. Additionally, it was shown that UA did not induce uterine proliferation or alter blood biochemical parameters. Based on these findings, we can conclude that UA has the potential to act as a potent estrogen receptor alpha (ERα) modulator and 27-HC antagonist. UA is safe to consume and is very well tolerated. This study further opens up the potential of UA as ER modulator and its benefits in estrogen-dependent tissues.