Abstract:
:Loss or decrease of wild type BRCA1 function, by either mutation or reduced expression, has a role in hereditary and sporadic human breast and ovarian cancers. We report here that the PI3K/AKT pathway is constitutively active in BRCA1-defective human breast cancer cells. Levels of phospho-AKT are sustained even after serum starvation in breast cancer cells carrying deleterious BRCA1 mutations. Knockdown of BRCA1 in MCF7 cells increases the amount of phospho-AKT and sensitizes cells to small molecule protein kinase inhibitors (PKIs) targeting the PI3K/AKT pathway. Restoration of wild type BRCA1 inhibits the activated PI3K/AKT pathway and de-sensitizes cells to PKIs targeting this pathway in BRCA1 mutant breast cancer cells, regardless of PTEN mutations. In addition, clinical PI3K/mTOR inhibitors, PI-103, and BEZ235, showed anti-proliferative effects on BRCA1 mutant breast cancer cell lines and synergism in combination with chemotherapeutic drugs, cisplatin, doxorubicin, topotecan, and gemcitabine. BEZ235 synergizes with the anti-proliferative effects of gemcitabine by enhancing caspase-3/7 activity. Our results suggest that the PI3K/AKT pathway can be an important signaling pathway for the survival of BRCA1-defective breast cancer cells and pharmacological inhibition of this pathway is a plausible treatment for a subset of breast cancers.
journal_name
Mol Carcinogjournal_title
Molecular carcinogenesisauthors
Yi YW,Kang HJ,Kim HJ,Hwang JS,Wang A,Bae Idoi
10.1002/mc.21905subject
Has Abstractpub_date
2013-09-01 00:00:00pages
667-75issue
9eissn
0899-1987issn
1098-2744journal_volume
52pub_type
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journal_title:Molecular carcinogenesis
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
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更新日期:2015-09-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.20701
更新日期:2011-03-01 00:00:00
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pub_type: 杂志文章
doi:10.1002/mc.22385
更新日期:2016-10-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
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更新日期:1992-01-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.21907
更新日期:2013-09-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.2940130109
更新日期:1995-05-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.22149
更新日期:2015-06-01 00:00:00
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更新日期:2015-11-01 00:00:00
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pub_type: 杂志文章
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更新日期:2003-04-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
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更新日期:1992-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2015-06-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.2940120205
更新日期:1995-02-01 00:00:00
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pub_type: 杂志文章
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更新日期:2015-09-01 00:00:00
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更新日期:2015-11-01 00:00:00
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更新日期:2016-04-01 00:00:00
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