Abstract:
:In the multistep progressive pathogenesis of human breast cancer, comedo ductal carcinoma in situ (DCIS) represents a preinvasive precursor lesion for therapy resistant invasive cancer. Human tissue derived cell culture models exhibiting molecular similarities to clinical DCIS facilitate an important preclinical mechanistic approach for evaluation of preventive efficacy of natural and synthetic chemopreventive compounds. Natural phytochemicals present in fresh fruits, vegetables and grain products are likely to offer protection against cancer. The clinical efficacy of these natural phytochemicals, however, depends on extrapolation, and is therefore equivocal. The present study determined whether the natural soy isoflavone genistein (GEN) inhibited aberrant proliferation in 184-B5/HER cells (a model for human comedo DCIS) and identified possible mechanisms responsible for its efficacy. Human reduction mammoplasty derived HER-2/neu oncogene expressing preneoplastic 184-B5/HER cells represented the experimental system. Flow cytometry and cellular epifluorescence based assays were utilized to quantitate the alterations in cell cycle progression, cellular apoptosis, and in the status of cell cycle regulatory and apoptosis-associated gene product expression. The 184-B5/HER cells exhibited specific immunofluorescence to p185HER, p53, EGFR, but not to ERalpha, thus resembling comedo DCIS. Treatment of 184-B5/HER cells with GEN resulted in a dose-dependent decrease in the viable cell population, increase in the G0/G1:S + G2/M ratio and enhancement of sub G0/G1 (apoptotic population). Exposure to the maximum cytostatic 10 microM dose of GEN down-regulated HER-2/neu mediated signal transduction as evidenced by a 73.9% decrease (p=0.001) in p185HER specific, and a 89.8% decrease (p=0.001) in phosphotyrosine specific immunofluorescence. The increase in G0/G1:S + G2/M ratio in response to the treatment with 10 microM GEN was associated with a 85.5% decrease (p=0.001) in immunoreactivity to PCNA and a 128.6% increase (p=0.004) in immunoreactivity to the cyclin dependent kinase inhibitor p16INK4. The induction of apoptosis by GEN was associated with a 52.8% decrease (p=0.001) in the immunoreactivity to antiapoptotic Bcl-2 and with a 195.9% (p=0.001) increase in the immunoreactivity to proapoptotic Bax. Thus, preventive efficacy of GEN in HER-2/neu+/ER- 184-B5/HER cells may be due to its ability to down-regulate HER-2/neu mediated signal transduction, increase the expression of the cyclin dependent kinase inhibitor p16INK4, and induce Bcl-2 dependent apoptosis. These data provide evidence that GEN may be a potential chemopreventive lead compound for human comedo DCIS. The 184-B5/HER cells, may therefore, provide a high throughput mechanistic bioassay to identify new chemopreventive agents for human breast cancer.
journal_name
Int J Oncoljournal_title
International journal of oncologyauthors
Katdare M,Osborne M,Telang NTkeywords:
subject
Has Abstractpub_date
2002-10-01 00:00:00pages
809-15issue
4eissn
1019-6439issn
1791-2423journal_volume
21pub_type
杂志文章abstract::Neuroblastoma (NB) is the most common extra-cranial solid tumor in children and despite aggressive therapy survival rates remain low. One of the contributing factors for low survival rates is aggressive tumor angiogenesis, which is known to increase due to radiation, one of the standard therapies for neuroblastoma. Th...
journal_title:International journal of oncology
pub_type: 杂志文章
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更新日期:2016-10-01 00:00:00
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journal_title:International journal of oncology
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journal_title:International journal of oncology
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journal_title:International journal of oncology
pub_type: 杂志文章
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journal_title:International journal of oncology
pub_type: 杂志文章
doi:
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pub_type: 杂志文章
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pub_type: 临床试验,杂志文章
doi:
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.3892/ijo.2014.2596
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journal_title:International journal of oncology
pub_type: 杂志文章
doi:
更新日期:2003-06-01 00:00:00
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journal_title:International journal of oncology
pub_type: 杂志文章
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更新日期:2012-04-01 00:00:00
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journal_title:International journal of oncology
pub_type: 杂志文章
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更新日期:1993-10-01 00:00:00
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journal_title:International journal of oncology
pub_type: 杂志文章
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更新日期:2003-08-01 00:00:00
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journal_title:International journal of oncology
pub_type: 杂志文章,评审
doi:
更新日期:2002-08-01 00:00:00
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pub_type: 杂志文章
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journal_title:International journal of oncology
pub_type: 杂志文章
doi:
更新日期:2004-09-01 00:00:00
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pub_type: 杂志文章
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journal_title:International journal of oncology
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doi:
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pub_type: 杂志文章
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更新日期:1997-10-01 00:00:00
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journal_title:International journal of oncology
pub_type: 杂志文章
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journal_title:International journal of oncology
pub_type: 杂志文章
doi:
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journal_title:International journal of oncology
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journal_title:International journal of oncology
pub_type: 杂志文章
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journal_title:International journal of oncology
pub_type: 杂志文章
doi:
更新日期:2007-07-01 00:00:00
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journal_title:International journal of oncology
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