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Targeting Breast Cancer Using RXR-Specific Retinoids

Survival curves of mice treated with two different rexinoids, bexarotene and LG100268 (left and right panels, respectively). Mice were treated with vehicle or agent (at 10mg/kg or 100mg/kg dose), as indicated for a period of one year.


Our research interests focus on the early detection and prevention of estrogen receptor (ER)-negative breast cancer. We are studying the mechanisms of breast cancer growth to support development of novel molecular-targets for cancer prevention and therapy.  Additionally, we are investigating tumor cell-signaling events in order to determine the biological pathways involved in tumorigenesis. It is our goal to define these signaling strategies using in vitro and in vivo models in order to develop future therapeutic agents. Breast cancer is the most common form of cancer and is the second most common cause of cancer-related death in women. Extensive studies have been conducted to identify agents for breast cancer prevention. Results from recent clinical trials have demonstrated that anti-estrogens significantly prevent the development of ER-positive breast cancer by more than 50%. Retinoids have been shown to prevent ER-negative mammary tumor development in animal models.  Bexarotene has been shown to partially prevent breast cancer development in mice, but has some toxic side effects. LG100268, a more selective rexinoid, has been developed and is expected to be a more effective chemopreventive agent for ER-negative breast cancer. We have analyzed the effects of LG100268 in the MMTV-ErbB2 mouse model. The results of this study demonstrate that the rexinoid LG100268 effectively prevents ER-negative mammary tumorigenesis in these mice. Additionally, LG100268 prevents the development of pre-malignant lesions, supporting its clinical usefulness as a chemopreventive agent. These results identify LG100268 as a potentially critical therapeutic agent for the future prevention of breast cancers in women determined to be at high-risk for breast cancer.

References:

  1. Wu K, Kim HT, Rodriquez JL, Hilsenbeck SG, Mohsin SK, Xu XC, Lamph WW, Kuhn JG, Green JE, Brown PH. Suppression of mammary tumorigenesis in transgenic mice by the RXR-selective retinoid, LGD1069. Cancer Epidemiol Biomarkers Prev 2002; 11:467-74.
  2. Wu K, Kim HT, Rodriquez JL, Munoz-Medellin D, Mohsin SK, Hilsenbeck SG, Lamph WW, Gottardis MM, Shirley MA, Kuhn JG, Green JE, Brown PH. 9-cis-Retinoic acid suppresses mammary tumorigenesis in C3(1)-simian virus 40 T antigen-transgenic mice. Clin Cancer Res 2000; 6:3696-704.
  3. Wu K, Zhang Y, Xu XC, Hill J, Celestino J, Kim HT, Mohsin SK, Hilsenbeck SG, Lamph WW, Bissonette R, Brown PH. The retinoid X receptor-selective retinoid, LGD1069, prevents the development of estrogen receptor-negative mammary tumors in transgenic mice. Cancer Res 2002; 62:6376-80.
  4.  Li Y, Zhang Y, Hill J, Shen Q, Kim HT, Xu X, Hilsenbeck SG, Bissonnette RP, Lamph WW, Brown PH. The Rexinoid LG100268 prevents the development of preinvasive and invasive estrogen receptor negative tumors in MMTV-erbB2 mice. Clin Cancer Res 13(20): 6224-31, 2008.
  5. Medina D, Kittrell F, Hill J, Zhang Y, Hilsenbeck SG, Bissonette R, Brown PH. Prevention of tumorigenesis in p53-null mammary epithelium by rexinoid bexarotene, tyrosine kinase inhibitor gefitinib, and celecoxib. Cancer Prev Res (Phila). 2009 Feb;2(2):168-74. Epub 2009 Jan 27.

Lab members working on this project:  

Abhijit Mazumdar, Ph.D., Ivan Uray, Ph.D., Jamal Hill, Senior Research Assistant and Yun Zhang, Senior Research Assistant.


© 2014 The University of Texas MD Anderson Cancer Center