In pursuit of effective therapeutic agents for the
estrogen receptor (ER)-negative
breast cancer, we previously showed that
bexarotene reduced mammary
tumor development by 75% in ErbB2 mice. To further improve the effectiveness of
breast cancer prevention, we have now investigated the effects of a combinatorial
therapy consisting of two
cancer preventive drugs. On the basis of the hypothesis, rexinoid
LG100268 plus
tamoxifen would more effectively prevent the development of both ER-positive and ER-negative
breast cancer. We treated p53-null mammary gland mice with
tamoxifen and
LG100268, individually and in combination. By 60 weeks of age, vehicle-treated mice developed
tumors in 52% of transplanted mammary glands, whereas mice treated with
tamoxifen and
LG100268 developed
tumors in only 13% of transplanted mammary glands. To further define the mechanistic effects of this combinatorial treatment, we investigated the effects of
tamoxifen and
LG100268 on mammary tissue
biomarkers. In mammary tissue harvested before
tumor development, the proliferation markers Ki67 and
cyclin D1 were significantly reduced in mice treated with the combination
therapy. In addition, the rexinoid target genes ABCA1 and ABCG1 were induced in both the rexinoid and combination treatment groups, whereas expression remained constant in
tamoxifen group. These results show that tamoxifen-LG100268 combinatorial treatment is more effective in preventing mammary
tumors than either agent alone. In addition, these studies have identified relevant tissue
biomarkers that can be used to show the effect of these agents on mammary tissue. These results support the development of clinical trials of
antiestrogen and rexinoid combinatorial
therapy for the prevention of patients with high-risk
breast cancer.