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

Abstract

-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. Nrf2; estrogen receptor; osteoblasts; antioxidant response element; lycopene; curcumin INCIDENCE RATES of breast and endometrial cancer have been rising in the last decades, due to increased exposure to estrogens resulting from changes in lifestyle (19,39). Thus, reduction of estrogen receptor activity is a major strategy for prevention of hormone-dependent malignancies. This preventive approach, however, must be implemented by taking into consideration that estrogens are beneficial to bone health. Women who enter menopause are at high risk for osteoporosis due to low blood levels of estrogens (42). Thus, since women today live longer after menopause than in a reproductive state, osteoporosis has become a serious threat to their health. To prevent hormone-dependent cancer without compromising bone health, specific estrogen receptor modulators (SERMs) have been developed (41). SERMs such as tamoxifen and raloxifen were successfully used for prevention of breast cancer in women who are at high risk for the disease and were also found to reduce the incidence of bone fractures (11, 54). However, for long-term prevention in the general population, dietary...

Carotenoids and apocarotenoids in cellular signaling related to cancer: A review

“…Thus, we examined the effects of lycopene derivatives on estrogenic activity in osteoblasts which are bone forming cells. We found that the diapocarotene‐dials, which inhibited estrogenic activity in cancer cells, did not inhibit and even stimulated estrogen receptor transactivation and the expression of estrogen‐responsive genes in the bone cells .…”

“…Moreover, these carotenoids inhibited transactivation of the estrogen response element by both estrogen receptor alpha and beta . In a more recent study, we found that synthetic diapocarotene‐dials also inhibited estrogen receptor transactivation in breast cancer cells . Although the action of estrogens in breast and endometrial cancer is harmful, it is beneficial for bone formation.…”

Effects of Glucosinolates from Turnip (Brassica rapa L.) Root on Bone Formation by Human Osteoblast‐Like MG‐63 Cells and in Normal Young Rats

“…Osteoblast differentiation and bone formation are controlled by the runt‐related transcription factor 2 (Runx2) and wingless‐int (Wnt) signaling pathway and are mediated by estrogenic activity (Raggatt and Partridge, ; Veprik et al , ). According to a recent report, sulforaphane, one of the isothiocyanate hydrolyzation products of glucoraphanin, was found to activate Runx2 and suppress the overproduction of radical oxygen species via regulation of nuclear factor erythroid 2‐related factor 2 (Nrf2) (Lin et al , ).…”

Using Topical Applications of Tamoxifen and a Combination of Phytonutrients Based on Breast MRI to Inhibit Estrogen-Related Proliferation of Human Breast Tissue

“…Searching for phytonutrients to prevent estrogenicinduced breast cancer is an alternative method for reducing the side effects of using chemical anti-estrogen drugs. According to Veprik et al [23] combining phytonutrients (carotenoid derivatives, polyphenols, and isothiocyanates) significantly inhibits estrogen response element (ERE) transactivation in breast cancer cells. In this study, we focused on the efficacy of tamoxifen and phytonutrients by examining the in vitro mammary glandular cell-proliferative response to estrogen.…”