Polyphenols, isothiocyanates, and carotenoid derivatives enhance estrogenic activity in bone cells but inhibit it in breast cancer cells

Polyphenols, isothiocyanates, and carotenoid derivatives enhance
estrogenic activity in bone cells but inhibit it in breast cancer cells. Am J
Physiol Endocrinol Metab 303: E815–E824, 2012. First published August
30, 2011; doi:10.1152/ajpendo.00142.2011.—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-

(ER
) 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 ER
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.