Retinoids are promising chemopreventive agents in animals and in humans, but because natural retinoids are relatively toxic, they are not generally used for cancer prevention. During the previous funding period we demonstrated that 9-cis retinoic acid (9cRA), which binds both the PAR and RXR retinoid receptors, suppresses mammary tumorigenesis in transgenic mice, but is too toxic for further development as a chemopreventive agent. We then demonstrated that retinoids like LGD1069 that selectively bind RXR (""""""""rexinoids"""""""") still inhibit breast cell growth and tumorigenesis, with minimal toxicity. These preclinical studies enabled us to design and open the first human cancer prevention clinical trial using rexinoids, now ongoing under a separate NIH grant. We also showed that rexinoids suppress breast cell growth predominantly via a G1 cell cycle block. The ability of both 9eRA and LGD1069 to suppress tumorigenesis was dependent on the specific oncogenic pathway--both were more effective in mice that develop breast cancer through overexpression oferbB2 than in mice that have Rb and P53 inactivated by expression of SV40 T antigen--but, unlike tamoxifen, both successfully prevented ER-negative as well as ER-positive tumors. We have also found that successful suppression of mammary tumorigenesis in the mice is associated with reduced proliferation and reduced Cox-2 expression in the mammary epithelial tissues, suggesting both biomarkers of prevention and potential targets for future therapies. We here hypothesize that rexinoids suppress breast carcinogenesis by modulating growth regulatory. proteins in normal breast cells, via RXR heterodimers with specific binding partners, and that combining rexinoids with selected complementary chemopreventive agents will more effectively prevent breast cancer. To test these hypotheses, we will: (1) Elucidate the mechanism by which rexinoids suppress the growth of normal breast cells, by defining the molecular basis for the G l cell cycle block and determining how rexinoids modulate critical growth regulators (cyclin D1, IGFBP-6, and Cox-2). (2) identify the critical RXR dimerization partners that mediate the tumor suppressive and growth suppressive effects of rexinoids, using co-immunoprecipitation and yeast-two-hybrid techniques. Individual RXR partners will then be selectively suppressed in breast cells to confirm their role in growth inhibition by rexinoids. (3) Determine whether combining a Cox2 inhibitor with a rexinoid more effectively prevents breast cancer than either agent alone in transgenic mice that develop ER-negative mammary cancer, and whether the combination of these agents increases modulation of specific biomarkers and inhibition of proliferation. These investigations will provide a foundation for development of an effective strategy to prevent ER-negative breast cancer in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078480-08
Application #
6879674
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Perloff, Marjorie
Project Start
1999-04-06
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
8
Fiscal Year
2005
Total Cost
$342,308
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Uray, Iván P; Dmitrovsky, Ethan; Brown, Powel H (2016) Retinoids and rexinoids in cancer prevention: from laboratory to clinic. Semin Oncol 43:49-64
Uray, Iván P; Rodenberg, Jennifer M; Bissonnette, Reid P et al. (2012) Cancer-preventive rexinoid modulates neutral lipid contents of mammary epithelial cells through a peroxisome proliferator-activated receptor ?-dependent mechanism. Mol Pharmacol 81:228-38
Mazumdar, Abhijit; Medina, Daniel; Kittrell, Francis S et al. (2012) The combination of tamoxifen and the rexinoid LG100268 prevents ER-positive and ER-negative mammary tumors in p53-null mammary gland mice. Cancer Prev Res (Phila) 5:1195-202
Howe, Louise R; Brown, Powel H (2011) Targeting the HER/EGFR/ErbB family to prevent breast cancer. Cancer Prev Res (Phila) 4:1149-57
Li, Yuxin; Shen, Qiang; Kim, Hee-Tae et al. (2011) The rexinoid bexarotene represses cyclin D1 transcription by inducing the DEC2 transcriptional repressor. Breast Cancer Res Treat 128:667-77
Uray, Iván P; Brown, Powel H (2011) Chemoprevention of hormone receptor-negative breast cancer: new approaches needed. Recent Results Cancer Res 188:147-62
Zhang, Guihong; Brewster, Abenaa; Guan, Baoxiang et al. (2011) Tumor-suppressor activity of RRIG1 in breast cancer. BMC Cancer 11:32
Brown, Powel H; Viner, Jaye L; Brewster, Abenaa et al. (2009) Conference Report: Seventh Annual AACR International Conference on Frontiers in Cancer Prevention Research. Cancer Prev Res (Phila) 2:995-8
Uray, Iván P; Shen, Qiang; Seo, Hye-Sook et al. (2009) Rexinoid-induced expression of IGFBP-6 requires RARbeta-dependent permissive cooperation of retinoid receptors and AP-1. J Biol Chem 284:345-53
Li, Y; Zhang, Y; Hill, J et al. (2008) The rexinoid, bexarotene, prevents the development of premalignant lesions in MMTV-erbB2 mice. Br J Cancer 98:1380-8

Showing the most recent 10 out of 23 publications