Proliferative response of ERalpha-positive breast cancer cells to 10 uM enterolactone, and the associated alteration in the transcriptomic landscape.

Abstract

Enterolactone (EL) is a product of gut-microbial metabolism of dietary plant lignans. Studies linking EL with breast cancer risk have bolstered investigations into its effects on the mammary epithelial cells, and the mechanisms thereof. While it binds to the estrogen receptor ; ER, its effect on the proliferation of mammary tumor cell lines is reportedly ambivalent; depending on its concentration. The genomic correlates of EL actions also remain unexplored. Here we have elaborately studied the effect of EL on proliferation of ER-positive, and ER-negative cell lines. 10 {micro}M EL significantly enhanced the growth of the ER-positive MCF-7 or T47D breast cancer cells, but not the ER-negative MDA-MB-231 or MDA-MB-453 cells. In MCF-7 cells, it significantly increased the expression of TFF1 mRNA, an estrogen-induced transcript. The binding of ER to the estrogen response element within the TFF1 locus further demonstrates the pro-estrogenic effect of 10 {micro}M EL. We further explored the genome-wide transcriptomic effect of 10 {micro}M EL. Analysis of RNA-seq data obtained from control- or 10 {micro}M EL treated-MCF-7 cells revealed modulation of expression of diverse sets of functionally related genes, which reflected cell cycle progression, rather than cell cycle arrest or apoptosis. The manner in which 10 {micro}M EL regulated the hallmark G2/M checkpoint, and estrogen-response-late genes correlated with proliferation inducing, and estrogen-like effects of EL on MCF-7 cells.