The overall objective of this preclinical research project is to determine efficacy of benzyl isothiocyanate (BITC), a constituent of many edible cruciferous vegetables, for prevention of breast cancer using animal models and to determine the mechanism of its anti-carcinogenic effect using MDA-MB-231 and MCF-7 human breast cancer cells as a model. Rationale for these studies derives from recent epidemiological data and the results of our preliminary studies. Epidemiological studies have concluded that cruciferous vegetable intake is inversely associated with breast cancer risk. Our preliminary studies led us to hypothesize that BITC may delay onset and/or progression of breast cancer due to its ability to cause p53- and Cdc25C-regulated G2/M phase cell cycle arrest and caspase-mediated apoptosis involving ROS generation and Bcl-2 family proteins. This hypothesis will be tested by the following specific aims:
Specific Aim 1 will determine the mechanism of BITC-mediated ROS generation, which is critical for apoptosis induction by BITC (preliminary data).
Specific Aim 2 will systematically determine the role of Bcl-2 family proteins and caspases in BITC- induced apoptosis.
In Specific Aim 3, experiments are designed to answer the questions whether expression of wild type p53 exacerbates BITC-mediated cell cycle arrest, and whether BITC-mediated down-modulation of Cdc25C protein is caused by redox modification of critical cysteine residue(s).
Specific Aim 4 will determine the effect of dietary BITC administration on growth of MDA-MB-231 and MCF-7 xenografts in vivo in nude mice.
Specific Aim 5 will determine the effect of dietary BITC administration on breast carcinogenesis using MMTV-neu transgenic mice.
In Specific Aims 4 and 5, tumor tissues from control and BITC treated mice will be analyzed for apoptosis index and levels of cell cycle and apoptosis regulating proteins to gain insights into the mechanism by which BITC may inhibit mammary carcinogenesis in vivo. In summary, the proposed studies will (a) define the mechanism by which BITC inhibits growth of human breast cancer cells, which may lead to identification of mechanism-based biomarkers potentially useful in future clinical trials, and (b) determine efficacy of BITC against breast cancer in animal models, which is a prerequisite for initiation of clinical trials to determine its activity against human breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129347-05
Application #
8119093
Study Section
Special Emphasis Panel (ZRG1-ONC-B (03))
Program Officer
Riscuta, Gabriela
Project Start
2007-09-07
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$273,686
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Sehrawat, Anuradha; Kim, Su-Hyeong; Hahm, Eun-Ryeong et al. (2017) Cancer-selective death of human breast cancer cells by leelamine is mediated by bax and bak activation. Mol Carcinog 56:337-348
Sehrawat, Anuradha; Singh, Shivendra V (2016) Short-form RON overexpression augments benzyl isothiocyanate-induced apoptosis in human breast cancer cells. Mol Carcinog 55:473-85
Sehrawat, Anuradha; Roy, Ruchi; Pore, Subrata K et al. (2016) Mitochondrial dysfunction in cancer chemoprevention by phytochemicals from dietary and medicinal plants. Semin Cancer Biol :
Sehrawat, Anuradha; Croix, Claudette St; Baty, Catherine J et al. (2016) Inhibition of mitochondrial fusion is an early and critical event in breast cancer cell apoptosis by dietary chemopreventative benzyl isothiocyanate. Mitochondrion 30:67-77
Kim, Su-Hyeong; Singh, Shivendra V (2015) The role of polycomb group protein Bmi-1 and Notch4 in breast cancer stem cell inhibition by benzyl isothiocyanate. Breast Cancer Res Treat 149:681-92
Antony, Marie L; Lee, Joomin; Hahm, Eun-Ryeong et al. (2014) Growth arrest by the antitumor steroidal lactone withaferin A in human breast cancer cells is associated with down-regulation and covalent binding at cysteine 303 of ?-tubulin. J Biol Chem 289:1852-65
Sehrawat, Anuradha; Sakao, Kozue; Singh, Shivendra V (2014) Notch2 activation is protective against anticancer effects of zerumbone in human breast cancer cells. Breast Cancer Res Treat 146:543-55
Sehrawat, Anuradha; Kim, Su-Hyeong; Vogt, Andreas et al. (2013) Suppression of FOXQ1 in benzyl isothiocyanate-mediated inhibition of epithelial-mesenchymal transition in human breast cancer cells. Carcinogenesis 34:864-73
Kim, Su-Hyeong; Sehrawat, Anuradha; Singh, Shivendra V (2013) Dietary chemopreventative benzyl isothiocyanate inhibits breast cancer stem cells in vitro and in vivo. Cancer Prev Res (Phila) 6:782-90
Antony, Marie Lue; Kim, Su-Hyeong; Singh, Shivendra V (2012) Critical role of p53 upregulated modulator of apoptosis in benzyl isothiocyanate-induced apoptotic cell death. PLoS One 7:e32267

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