Receptor-selective retinoids inhibit the growth of normal and malignant breast cells by inducing G1 cell cycle blockade

Abstract

Despite advances in treatment, breast cancer continues to be the second leading cause of cancer mortality in women. Statistics suggest that while focus on treatment should continue, chemopreventive approaches should also be pursued. Previous studies have demonstrated that naturally occurring retinoids such as 9-cis retinoic acid (9cRA) can prevent breast cancer in animal models. However, these studies have also shown that these compounds are too toxic for general use. Work from our laboratory showed that an RXR-selective retinoid LGD1069 prevented tumor development in animal models of cancer with reduced toxicity as compared to an RAR-selective retinoid TTNPB. In the present study, we investigated the mechanisms by which receptor-selective retinoids inhibit the growth of normal and malignant breast cells. Our results demonstrate that the synthetic retinoids tested are as effective as 9cRA in suppressing the growth of normal human mammary epithelial cells (HMECs) and estrogen receptor-positive (ER-positive) breast cancer cells. Although the receptor-selective retinoids induce minimal amounts of apoptosis in T47D breast cancer cells, the predominant factor that leads to growth arrest is G1 cell cycle blockade. Our data indicate that this blockade results from the downregulation of Cyclin D1 and Cyclin D3, which in turn causes Rb hypophosphorylation. Non-toxic retinoids that are potent inducers of cell cycle arrest may be particularly useful for the prevention of breast cancer.

The rexinoid, bexarotene, prevents the development of premalignant lesions in MMTV-erbB2 mice

“…The proportion of cells that undergo apoptosis was not increased after 4 months treatment of bexarotene ( Figure 2B). This is consistent with our previous results, in which rexinoid did not promote apoptosis in normal mammary epithelial cells (Wu et al, 2006). Christov et al (2007) found that short-term treatment with high dose of bexarotene (150 mg kg À1 ) induced apoptosis in methylnitrosourea-induced mammary cancers in rat (Christov et al, 2007).…”

“…This is also supported by our published data showing that the proliferation inhibition by bexarotene was more profound in normal mammary epithelial cells than in breast cancer cells (Wu et al, 2006). Previous studies showed that bexarotene inhibited the breast cancer cell proliferation in vitro (Wu et al, 2002a) and carcinogen-inducted mammary tumour growth in vivo (Bischoff et al, 1999).…”

“…Sporn's group also found that the rexinoid LG100268 did not induce apoptosis in vivo and in vitro, although it did synergise with arzoxifene to promote apoptosis (Suh et al, 2002;Rendi et al, 2004). Recent data showed that both rexinoids (bexarotene and LG100268) significantly downregulate cyclin D1 expression and block cell cycle progression in normal and malignant breast cells (Wu et al, 2006). In addition, Yu et al (2006) and Landis et al (2006) demonstrated that mice lacking cyclin D1 activity were protected from developing erbB2-induced mammary tumours.…”

“…Previous results have shown that bexarotene significantly inhibits cell growth in normal mammary epithelial cells (Wu et al, 2006). Proliferation inhibition and apoptosis promotion are two major causes of growth suppression.…”

“…Similarly, tumours developed in MMTV-erbB2 transgenic mice also arise through a multistage process (Kosanke et al, 2004). Bexarotene inhibits cell proliferation in normal human mammary epithelial cells (Wu et al, 2006), suggesting that it will prevent tumour formation at the early stages during the chronic multistage carcinogenesis. In this study, we investigated the ability of bexarotene to prevent the development of premalignant lesions in MMTV-erbB2 mice.…”