کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5525720 1546684 2017 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Original ArticleCRISPR-mediated targeting of HER2 inhibits cell proliferation through a dominant negative mutation
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
Original ArticleCRISPR-mediated targeting of HER2 inhibits cell proliferation through a dominant negative mutation
چکیده انگلیسی


- Genomic targeting of HER2 in breast cancer cells by CRISPR/Cas9 inhibited cell growth and tumorigenicity.
- Effect of CRISPR/Cas9 targeting was enhanced by PARP inhibitors.
- CRISPR targeting of HER2 unexpectedly resulted in a dominant negative mutation.

With the discovery of the CRISPR/Cas9 technology, genome editing could be performed in a rapid, precise and effective manner. Its potential applications in functional interrogation of cancer-causing genes and cancer therapy have been extensively explored. In this study, we demonstrated the use of the CRISPR/Cas9 system to directly target the oncogene HER2. Directing Cas9 to exons of the HER2 gene inhibited cell growth in breast cancer cell lines that harbor amplification of the HER2 locus. The inhibitory effect was potentiated with the addition of PARP inhibitors. Unexpectedly, CRISPR-induced mutations did not significantly affect the level of HER2 protein expression. Instead, CRISPR targeting appeared to exert its effect through a dominant negative mutation. This HER2 mutant interfered with the MAPK/ERK axis of HER2 downstream signaling. Our work provides a novel mechanism underlying the anti-cancer effects of HER2-targeting by CRISPR/Cas9, which is distinct from the clinical drug Herceptin. In addition, it opens up the possibility that incomplete CRISPR targeting of certain oncogenes could still have therapeutic value by generation of dominant negative mutants.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cancer Letters - Volume 385, 28 January 2017, Pages 137-143
نویسندگان
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