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

Abstract

Retinoids, vitamin A analogues that bind to retinoic acid receptor (RAR) or retinoid X receptor (RXR), play important roles in regulating cell proliferation, apoptosis, and differentiation. Recently, RXR-selective ligands, also referred to as rexinoids, have been investigated as potential chemopreventive agents for breast cancer. Our previous studies demonstrated that the rexinoid bexarotene significantly prevented ER-negative mammary tumourigenesis with less toxicity than naturally occurring retinoids in animal models. To determine whether bexarotene prevents cancer at the early stages during the multistage process of mammary carcinogenesis, we treated MMTV-erbB2 mice with bexarotene for 2 or 4 months. The development of preinvasive mammary lesions such as hyperplasias and carcinoma-in-situ was significantly inhibited. This inhibition was associated with reduced proliferation, but no induction of apoptosis. We also examined the regulation of a number of rexinoid-modulated genes including critical growth and cell cycle regulating genes using breast cell lines and mammary gland samples from mice treated with rexinoids. We showed that two of these genes (DHRS3 and DEC2) were modulated by bexarotene both in vitro and in vivo. Identification of these rexinoid-modulated genes will help us understand the mechanism by which rexinoid prevents cancer. Such rexinoid-regulated genes also represent potential biomarkers to assess the response of rexinoid treatment in clinical trials.

Bexarotene Induces Cellular Senescence in MMTV-Neu Mouse Model of Mammary Carcinogenesis

“…Potential implementation of much lower doses of bexarotene (20, 10 mg/kg bw) may distinguish cellular senescence from apoptosis and cell proliferation, as has been reported for in vitro studies. Bexarotene was highly efficacious in inducing cellular senescence in TEBs, which have high proliferation activity and are considered places of origin of most mammary tumors, thus supporting our data and those of others that retinoids and rexinoids are more efficacious in inhibiting early than late (MIN, tumors) stages of mammary carcinogenesis (16,23).…”

“…Our data confirm previous studies of Brown's group, which found that bexarotene suppressed mammary carcinogenesis and tumor growth in MMTV-Neu mice and that this was associated with inhibition of cell proliferation (12,16). For assessment of apoptosis, we used the TUNEL assay, whereas Brown's group used the caspase-3 assay that may explain the differences in the percentage of cells in apoptosis between their and our study.…”

“…Here, we used the MMTV-Neu mammary carcinogenesis model in mice and breast cancer cell lines to determine potential target genes associated with the bexaroteneinduced cellular senescence. Previous studies have shown that bexarotene suppressed mammary carcinogenesis in MMTV-Neu mice by a dose-dependent manner, and this was associated with no changes in ErbB2 expression, but with inhibition of cell proliferation (12,16,27). The combination of bexarotene with the Cox-2 inhibitor celecoxib further increased inhibitory effects on mammary carcinogenesis (28).…”

“…Tissues free of tumors were also collected from abdominal and thoracic mammary glands and fixed in formalin or frozen in liquid nitrogen. These were used for identification of hyperplastic (atypical hyperplasia, AH) and premalignant (minimal intraepithelial neoplasia, MIN) lesions, as described by Brown and colleagues (12,16).…”

“…Rexinoids are ligands of retinoid X receptors a, b, g (RXRs a, b, g) and exert their biologic effects by receptor-dependent and -independent mechanisms (10)(11)(12). The cellular effects of retinoids and rexinoids are primarily associated with inhibition of proliferation and induction of differentiation (13)(14)(15)(16).…”