Estrogen is a causative factor for the development of breast cancer. It remains critically important to identify novel therapies that prevent estrogen carcinogenesis without significant toxicity. Induction of detoxifying enzymes is considered an important mechanism of protection against estrogen-associated carcinogenesis because they facilitate removal of toxic estrogens. The levels of detoxifying enzymes are determined by the key transcription factor Nrf2 factor that binds to the antioxidant response element in the promoters of genes encoding detoxification enzymes to increase transcription. Thus, a chemoprevention goal is to enhance Nrf2 function. Our preliminary studies show a novel role for shikonin (a bioactive agent extracted from the Shikon plant) in breast cancer prevention via a dual mechanism of action. Shikonin inhibits estrogen signaling and induces Nrf2 expression. This unique chemopreventive activity inhibits transformation from normal mammary epithelial to malignant states and prevents estrogen- dependent tumor formation. Based on these findings, we hypothesize that shikonin activates Nrf2 function leading to increased detoxifying enzyme expression. Consequently, these enzymes will remove genotoxic estrogen, and reduce DNA damage. We will test this hypothesis by determining 1) mechanisms of estrogen and shikonin in regulating expression of Nrf2 and detoxifying enzymes;2) ability of shikonin to impact the Nrf2-dependent chemoprotection pathway;and 3) the role of Nrf2 in shikonin chemoprevention of mammary tumorigenesis using Nrf2 knockout mice. The results obtained from this proposal reveal that shikonin reverses the estrogen action in a novel way by reducing estrogen suppression of Nrf2 expression. These studies demonstrate that shikonin is a novel dietary agent with great potential as a breast cancer preventative.

Public Health Relevance

Our proposed studies identify that a novel dietary agent, shikonin (a bioactive component extracted from the Shikon plant), prevents breast cancer by activation of Nrf2-dependet detoxifying enzymes in vitro and in vivo.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-OTC-K (03))
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Malone, Winfred F
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University of Maryland Baltimore
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Lo, Pang-Kuo; Yao, Yuan; Lee, Ji Shin et al. (2018) LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer. Elife 7:
Wolfson, Benjamin; Lo, Pang-Kuo; Yao, Yuan et al. (2018) Impact of miR-140 Deficiency on Non-Alcoholic Fatty Liver Disease. Mol Nutr Food Res 62:e1800189
Lo, Pang-Kuo; Zhou, Qun (2018) Emerging techniques in single-cell epigenomics and their applications to cancer research. J Clin Genom 1:
Wolfson, Benjamin; Zhang, Yongshu; Gernapudi, Ramkishore et al. (2017) A High-Fat Diet Promotes Mammary Gland Myofibroblast Differentiation through MicroRNA 140 Downregulation. Mol Cell Biol 37:
Lo, Pang-Kuo; Zhang, Yongshu; Yao, Yuan et al. (2017) Tumor-associated myoepithelial cells promote the invasive progression of ductal carcinoma in situ through activation of TGF? signaling. J Biol Chem 292:11466-11484
Duru, Nadire; Gernapudi, Ramkishore; Lo, Pang-Kuo et al. (2016) Characterization of the CD49f+/CD44+/CD24- single-cell derived stem cell population in basal-like DCIS cells. Oncotarget 7:47511-47525
Duru, Nadire; Zhang, Yongshu; Gernapudi, Ramkishore et al. (2016) Loss of miR-140 is a key risk factor for radiation-induced lung fibrosis through reprogramming fibroblasts and macrophages. Sci Rep 6:39572
Lo, Pang-Kuo; Wolfson, Benjamin; Zhou, Qun (2016) Cancer stem cells and early stage basal-like breast cancer. World J Obstet Gynecol 5:150-161
Lo, Pang-Kuo; Wolfson, Benjamin; Zhou, Qun (2016) Cellular, physiological and pathological aspects of the long non-coding RNA NEAT1. Front Biol (Beijing) 11:413-426
Lo, Pang-Kuo; Zhang, Yongshu; Wolfson, Benjamin et al. (2016) Dysregulation of the BRCA1/long non-coding RNA NEAT1 signaling axis contributes to breast tumorigenesis. Oncotarget 7:65067-65089

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