NF-kappaB-mediated HER2 overexpression in radiation-adaptive resistance.
The molecular mechanisms governing acquired tumor resistance during radiotherapy remain to be elucidated. In breast cancer patients, overexpression of HER2 (human epidermal growth factor receptor 2) is correlated with aggressive tumor growth and increased recurrence. In the present study, we demonstrate that HER2 expression can be induced by radiation in breast cancer cells with a low basal level of HER2. Furthermore, HER2-postive tumors occur at a much higher frequency in recurrent invasive breast cancer (59%) compared to the primary tumors (41%). Interestingly, NF-kappaB is required for radiation-induced HER2 transactivation. HER2 was found to be co-activated with basal and radiation-induced NF-kappaB activity in radioresistant but not radiosensitive breast cancer cell lines after long-term radiation exposure, indicating that NF-kappaB-mediated HER2 overexpression is involved in radiation-induced repopulation in heterogeneous tumors. Finally, we found that inhibition of HER2 resensitizes the resistant cell lines to radiation. Since HER2 is shown to activate NF-kappaB, our data suggest a loop-like HER2-NF-kappaB-HER2 pathway in radiation-induced adaptive resistance in breast cancer cells.
Cao
Ning
N
Division of Molecular Radiobiology and Graduate Program of Radiation and Cancer Biology, Purdue University School of Health Sciences, West Lafayette, IN 47907, USA.
Li
Shiyong
S
Wang
Zhaoqing
Z
Ahmed
Kazi Mokim
KM
Degnan
Michael E
ME
Fan
Ming
M
Dynlacht
Joseph R
JR
Li
Jian Jian
JJ
D000222:Adaptation, Physiological / Q000235:genetics*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control / Q000532:radiotherapy; D045744:Cell Line, Tumor; D005720:Gamma Rays / Q000009:adverse effects; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D018734:Genes, erbB-2 / Q000235:genetics* / Q000528:radiation effects*; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000528:radiation effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics*; D012008:Recurrence; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects; D015854:Up-Regulation / Q000528:radiation effects
D001549:Benzamides; D016328:NF-kappa B; D034741:RNA, Small Interfering; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide