While exposure to
estrogens is a major risk factor of breast and
endometrial cancer, it well established that
estrogens are beneficial for bone health. We have previously shown that
carotenoids inhibit
estrogen signaling in breast and
endometrial cancer cells. The aim of this study was to compare the effects of various
phytonutrients, (
carotenoid derivatives,
polyphenols,
isothiocyanates) on estrogenic activity in
breast cancer cells and osteoblast-like cells. All the tested
phytonutrients inhibited
estrogen response element (ERE) transactivation in
breast cancer cells. In contrast, these compounds either did not affect or enhanced ERE activity and the expression of several bone-forming genes. These results were obtained using two osteoblast-like cell lines, MG-63 human
osteosarcoma cells stably transfected with
estrogen receptor-α (ERα) and MC3T3-E1 mouse calvaria-derived cells expressing endogenous ER.
Phytonutrients-induced ERE inhibition in
breast cancer cells, and its potentiation in osteoblast-like cells were associated both with a decrease and a rise in total and nuclear ERα levels, respectively.
Phytonutrients activated the electrophile/antioxidant response element (EpRE/ARE) transcription system to various extents in both
cancer and bone cell lines. Overexpression of Nrf2, the major EpRE/ARE activating
transcription factor, mimicked the effects of
phytonutrients, causing inhibition and enhancement of ERE transactivation in
breast cancer cells and in osteoblast-like cells, respectively. Moreover, reduction in Nrf2 levels by RNAi led to a decrease in the
phytonutrient potentiation of ERE activity transactivation in osteoblast-like cells. These findings suggest that the enhancement and inhibition of
estrogen signaling by
phytonutrients in bone-derived cells and
breast cancer cells, respectively, is partially mediated by the activation of the Nrf2/ARE system.