PPM1H Is a p27 Phosphatase Implicated in Trastuzumab Resistance
| العنوان: | PPM1H Is a p27 Phosphatase Implicated in Trastuzumab Resistance |
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| المؤلفون: | Wei Zhou, Samuel Aparicio, Xander Munroe, Somasekar Seshagiri, Klaus P. Hoeflich, Si Tuen Lee-Hoeflich, Jeremy Stinson, Don Dowbenko, James Lee, Jeffrey Eastham-Anderson, Li Li, David Davis, Kanan Pujara, Gulisa Turashvili, Sara M. Chan, Ajay Pandita, Mark X. Sliwkowski, Howard M. Stern, Peter M. Haverty, Karen A. Gelmon, Thinh Pham |
| المصدر: | Cancer Discovery. 1:326-337 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Proteasome Endopeptidase Complex, Receptor, ErbB-2, Phosphatase, Breast Neoplasms, Antibodies, Monoclonal, Humanized, Bioinformatics, Breast cancer, RNA interference, Trastuzumab, Cell Line, Tumor, Phosphoprotein Phosphatases, Humans, Medicine, skin and connective tissue diseases, Cell Line, Transformed, Gene knockdown, Oncogene, business.industry, Tumor Suppressor Proteins, Cancer, Genes, erbB-2, medicine.disease, HEK293 Cells, Oncology, Drug Resistance, Neoplasm, Cancer cell, Cancer research, Female, business, Cyclin-Dependent Kinase Inhibitor p27, medicine.drug |
| الوصف: | The HER2 oncogene is overexpressed or amplified in 20% of breast cancers. HER2-positive cancer historically portends a poor prognosis, but the HER2-targeted therapy trastuzumab mitigates this otherwise ominous distinction. Nevertheless, some patients suffer disease recurrence despite trastuzumab, and metastatic disease remains largely incurable due to innate and acquired resistance. Thus, understanding trastuzumab resistance remains an unmet medical need. Through RNA interference screening, we discovered that knockdown of the serine/threonine phosphatase PPM1H confers trastuzumab resistance via reduction in protein levels of the tumor suppressor p27. PPM1H dephosphorylates p27 at threonine 187, thus removing a signal for proteasomal degradation. We further determined that patients whose tumors express low levels of PPM1H trend towards worse clinical outcome on trastuzumab. Identifying PPM1H as a novel p27 phosphatase reveals new insight into how cancer cells destabilize a well-recognized tumor suppressor. Furthermore, low PPM1H expression may identify a subset of HER2-positive tumors that are harder to treat. Significance: PPM1H is identified as a phosphatase impacting p27 stability. Low expression of PPM1H may be associated with poor outcome in breast cancer. Cancer Discovery; 1(4); 326–337. ©2011 AACR. Read the Commentary on this article by Aceto and Bentires-Alj, p. 285 This article is highlighted in the In This Issue feature, p. 275 |
| تدمد: | 2159-8290 2159-8274 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9eec65bbc4a25ee2bad39007efff785d https://doi.org/10.1158/2159-8290.cd-11-0062 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....9eec65bbc4a25ee2bad39007efff785d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21598290 21598274 |
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