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Chemoprevention of ER-negative breast cancer using rexinoid LG100268
Background and objective: S elective estrogen receptor (ER) modulators (SERMs) can effectively prevent the development of ER-positive breast cancer. However, they have no effect in reducing the risk of ER-negative breast cancer and are quite toxic. R exinoids, compounds that selectively bind RXR, have been shown to prevent mammary tumorigenesis with reduced toxicity. Our previous studies demonstrated that rexinoid LGD1069 suppresses the growth of ER-negative breast cells and inhibits the development of ER-negative mammary tumor in animal models. However, LGD1069 does not totally prevent mammary tumorigenesis and still has side effects. Recently, a more specific rexinoid, LG100268, has been developed and shown to synergize with arzoxifene to prevent mammary tumorigenesis in rat models. Thus, the proposed study is to determine the chemopreventive effect of this rexinoid in preventing ER-negative breast cancer. Hypothesis: We hypothesize that the rexinoid LG100268 will effectively prevents ER-negative breast ca rcinogenesis with minor or no toxicity and it prevents cancer by modulating genes specifically regulated by RXR transcription factors. Specific aims: W e propose to 1) determine whether LG100268 suppresses ER-negative mammary tumorigenesis in mice ; 2) examine the effect of the rexinoid treatment on the development of premalignant mammary lesion s; and 3) identify rexinoid - regulated genes and determine whether these genes are critical for the cancer preventive effect of this rexinoid . Study design: The chemopreventive effect of LG100268 will first be tested in MMTV-erbB2 mice which spontaneously develop ER-negative breast cancers. We will then determine the effect on the development of premalignant lesions using mice treated for 2 or 4 months. We will monitor the tumor development and toxicity in these mice. LG100268-reguated genes will be identified by performing Affymetrix microarray analyses. Transfection assays will be used to test the functional involvement of these genes in the chemopreventive effect of LG100268. Potential outcomes and benefits of the research: The results of the proposed study will determine whether this novel rexinoid prevents the development of breast cancer, and will also help elucidate the underlying mechanisms and provide the basic scientific rationale to develop more effective and less toxic chemopreventive agents for ER-negative breast cancer.
Although anti-estrogens significantly suppress the development of estrogen receptor (ER)-positive breast cancer, they have no effect in reducing the risk of ER-negative breast cancer which accounts for one third of breast cancers. R exinoids, compounds that selectively bind RXR, have been shown to prevent breast cancer development with less toxicity than naturally occurring retinoids. We found that the rexinoid LGD1069 effectively prevented ER-negative breast cancer development in animal models. However, LGD1069 does not totally prevent breast cancer and still has side effects. LG100268 is a more specific RXR-selective rexinoid that has less toxicity than LGD1069 and has been shown to synergize with anti-estrogens to kill breast cancer cells. Thus, the proposed study is to determine whether this new rexinoid prevents the development of ER-negative breast cancer. We hypothesize that the novel rexinoid LG100268 will effectively prevent the development of ER-negative breast cancer with little or no toxicity. W e propose to: 1) determine whether LG100268 suppresses ER-negative breast cancer development in mice; 2) examine the effect of LG100268 treatment on the development of premalignant breast lesion s; and 3) identify LG100268-regulated genes and determine whether these genes are critical for the anti-cancer activity of LG100268 . We will first test the cancer preventive effect of LG100268 using MMTV-erbB2 transgenic mice which spontaneously develop ER-negative breast cancer. We will next determine the effect on the development of premalignant lesions using mice treated for 2 or 4 months. We will determine how LG100268 affects the incidence of non-invasive breast lesions and the growth of breast cells using mammary glands from these mice. We will also use Affymetrix microarray analysis to identify LG100268-regulated genes. The tumor suppressive role of these genes will be further investigated by modulating the expression of these genes in breast cells. The results of the proposed study will determine whether this novel rxinoid prevents the development of ER-negative breast cancer, and will also help elucidate the underlying mechanisms by which rexinoids prevent cancer. These studies will provide the basic scientific rationale to develop more effective and less toxic anti-cancer agents for the p revention of ER-negative breast cancer.