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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA157779-02
Application #
8685189
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Malone, Winfred F
Project Start
2013-07-01
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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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
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Eades, Gabriel; Wolfson, Benjamin; Zhang, Yongshu et al. (2015) lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6. Mol Cancer Res 13:330-8

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