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Inhibition of RelB by 1,25‐dihydroxyvitamin D 3 promotes sensitivity of breast cancer cells to radiation
Author(s) -
Mineva Nora D.,
Wang Xiaobo,
Yang Sanghwa,
Ying Haoqiang,
Xiao ZhiXiong J.,
Holick Michael F.,
Sonenshein Gail E.
Publication year - 2009
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21765
Subject(s) - relb , cancer research , breast cancer , gene knockdown , cancer cell , cancer , ectopic expression , medicine , biology , apoptosis , cell culture , nfkb1 , gene , transcription factor , biochemistry , genetics
Aberrant constitutive expression of the NF‐κB c‐Rel and RelA subunits in breast cancer cells was shown to promote their survival. Recently, we demonstrated that aggressive breast cancers constitutively express high levels of the RelB subunit, which promotes their more invasive phenotype via induction of the BCL2 gene. As these cancers are frequently resistant to therapy, here we tested the hypothesis that RelB promotes their survival. High RelB expressing Hs578T and MDA‐MB‐231 breast cancer cells were more resistant to γ‐radiation than MCF7 and ZR‐75 cells, which express lower RelB levels. Knockdown of RelB in Hs578T led to decreased survival in response to γ‐irradiation, while conversely ectopic expression of RelB in MCF7 cells protected these cells from radiation. Similar data were obtained upon treatment of Hs578T or MCF7 cells with the chemotherapeutic agent doxorubicin. High serum levels of 25‐hydroxyvitamin D are associated with decreased breast cancer risk and mortality, although, the mechanisms of its protective actions have not been fully elucidated. Treatment of Hs578T and Her‐2/neu‐driven NF639 cells with 1,25‐dihydroxyvitamin D 3 decreased RelB/RELB gene expression and levels of pro‐survival targets Survivin, MnSOD and Bcl‐2, while increasing their sensitivity to γ‐irradiation. Thus, RelB, which promotes survival and a more highly invasive phenotype of breast cancer cells, is a target of 1,25‐dihydroxyvitamin D 3 , providing one mechanism for the observed protective role of 25‐hydroxyvitamin D in patients with breast cancer. J. Cell. Physiol. 220: 593–599, 2009. © 2009 Wiley‐Liss, Inc.