SH3BGRL confers innate drug resistance in breast cancer by stabilizing HER2 activation on cell membrane
Abstract Background HER2-positive breast cancer is usually associated to the more aggressive progression and the worse prognosis, but the mechanism underlying the innate resistance to HER2-targeted therapy remains elusive. The scaffold protein SH3-domain-binding glutamic acid-rich protein-like prote...
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doaj-3f84a2e1c12a4e5f937947bcf7d93bed2020-11-25T02:18:33ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662020-05-0139111710.1186/s13046-020-01577-zSH3BGRL confers innate drug resistance in breast cancer by stabilizing HER2 activation on cell membraneHui Li0Mingming Zhang1Yanli Wei2Farhan Haider3Yitong Lin4Wen Guan5Yanbin Liu6Shaoyang Zhang7Ronghua Yuan8Xia Yang9Shulan Yang10Haihe Wang11Centre for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen UniversityCentre for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityThe Second Hospital of Jilin UniversityDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of General Surgery, The Second Affiliated Hospital of Nantong University, Nantong UniversityDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityCentre for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityAbstract Background HER2-positive breast cancer is usually associated to the more aggressive progression and the worse prognosis, but the mechanism underlying the innate resistance to HER2-targeted therapy remains elusive. The scaffold protein SH3-domain-binding glutamic acid-rich protein-like protein (SH3BGRL) is indicated as a tumor suppressor in some cancers, but it is highly expressed in breast cancers. Here we characterized the tumorigenic function of SH3BGRL in HER2-expressing breast cancer cells and the subsequent effect in HER2-targeted therapies. Methods The interaction of SH3BGRL to HER2 were characterized with various truncated SH3BGRL mutants by immunoprecipitation and molecule docking simulation. The physiological roles of SH3BGRL interacting with HER2 in tumor progression and therapy implication were characterized by gain and loss of function approaches in vitro and in vivo. Immunohistochemistry was used for detections of SH3BGRL and p-HER2 (Y1196) expressions in xenografted tumors and human breast cancer tissues. Clinical relevance of SH3BGRL expression with HER2 was validated with both breast patient sample and the public data analyses. Results Our results demonstrated that SH3BGRL directly binds with HER2 on cell membrane via its motifs α1, α2 helixes and β3 sheet, which postpones HER2 internalization upon EGF stimulation. Consequently, the association between SH3BGRL and HER2 contributed to the prolonged HER2 phosphorylation at specific tyrosine sites, especially at Y1196, and their downstream signaling activation. The relevance between SH3BGRL expression and p-HER2 (Y1196) phosphorylation was validated in both xenografted tumors and the breast cancer patient tissues. Mechanistically, SH3BGRL promoted breast tumor cell proliferation and survival, while reduced the cell sensitivity to anti-tumor drugs, especially to the HER2-targeted drugs. In contrast, Silencing SH3BGRL or inhibiting its downstream signals efficiently induced apoptosis of breast tumor cells with HER2 and SH3BGRL doubly positive expression. Database analysis also highlighted that SH3BGRL is a poor prognostic marker, especially for HER2-positive breast cancers. Conclusions Our results disclose SH3BGRL as a novel posttranslational modulator of HER2 hyperactivation, which can lead to the intrinsic resistance to HER2-targeted therapy. SH3BGRL would be a pivotal therapy target and a diagnostic marker to HER2-positve patients. Thus, targeting SH3BGRL or the downstream signaling could relieve the innate resistance to some HER2-tageted therapies for both HER2 and SH3BGRL-postive breast cancers.http://link.springer.com/article/10.1186/s13046-020-01577-zSH3BGRLHER2Breast cancerDrug resistance |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hui Li Mingming Zhang Yanli Wei Farhan Haider Yitong Lin Wen Guan Yanbin Liu Shaoyang Zhang Ronghua Yuan Xia Yang Shulan Yang Haihe Wang |
spellingShingle |
Hui Li Mingming Zhang Yanli Wei Farhan Haider Yitong Lin Wen Guan Yanbin Liu Shaoyang Zhang Ronghua Yuan Xia Yang Shulan Yang Haihe Wang SH3BGRL confers innate drug resistance in breast cancer by stabilizing HER2 activation on cell membrane Journal of Experimental & Clinical Cancer Research SH3BGRL HER2 Breast cancer Drug resistance |
author_facet |
Hui Li Mingming Zhang Yanli Wei Farhan Haider Yitong Lin Wen Guan Yanbin Liu Shaoyang Zhang Ronghua Yuan Xia Yang Shulan Yang Haihe Wang |
author_sort |
Hui Li |
title |
SH3BGRL confers innate drug resistance in breast cancer by stabilizing HER2 activation on cell membrane |
title_short |
SH3BGRL confers innate drug resistance in breast cancer by stabilizing HER2 activation on cell membrane |
title_full |
SH3BGRL confers innate drug resistance in breast cancer by stabilizing HER2 activation on cell membrane |
title_fullStr |
SH3BGRL confers innate drug resistance in breast cancer by stabilizing HER2 activation on cell membrane |
title_full_unstemmed |
SH3BGRL confers innate drug resistance in breast cancer by stabilizing HER2 activation on cell membrane |
title_sort |
sh3bgrl confers innate drug resistance in breast cancer by stabilizing her2 activation on cell membrane |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2020-05-01 |
description |
Abstract Background HER2-positive breast cancer is usually associated to the more aggressive progression and the worse prognosis, but the mechanism underlying the innate resistance to HER2-targeted therapy remains elusive. The scaffold protein SH3-domain-binding glutamic acid-rich protein-like protein (SH3BGRL) is indicated as a tumor suppressor in some cancers, but it is highly expressed in breast cancers. Here we characterized the tumorigenic function of SH3BGRL in HER2-expressing breast cancer cells and the subsequent effect in HER2-targeted therapies. Methods The interaction of SH3BGRL to HER2 were characterized with various truncated SH3BGRL mutants by immunoprecipitation and molecule docking simulation. The physiological roles of SH3BGRL interacting with HER2 in tumor progression and therapy implication were characterized by gain and loss of function approaches in vitro and in vivo. Immunohistochemistry was used for detections of SH3BGRL and p-HER2 (Y1196) expressions in xenografted tumors and human breast cancer tissues. Clinical relevance of SH3BGRL expression with HER2 was validated with both breast patient sample and the public data analyses. Results Our results demonstrated that SH3BGRL directly binds with HER2 on cell membrane via its motifs α1, α2 helixes and β3 sheet, which postpones HER2 internalization upon EGF stimulation. Consequently, the association between SH3BGRL and HER2 contributed to the prolonged HER2 phosphorylation at specific tyrosine sites, especially at Y1196, and their downstream signaling activation. The relevance between SH3BGRL expression and p-HER2 (Y1196) phosphorylation was validated in both xenografted tumors and the breast cancer patient tissues. Mechanistically, SH3BGRL promoted breast tumor cell proliferation and survival, while reduced the cell sensitivity to anti-tumor drugs, especially to the HER2-targeted drugs. In contrast, Silencing SH3BGRL or inhibiting its downstream signals efficiently induced apoptosis of breast tumor cells with HER2 and SH3BGRL doubly positive expression. Database analysis also highlighted that SH3BGRL is a poor prognostic marker, especially for HER2-positive breast cancers. Conclusions Our results disclose SH3BGRL as a novel posttranslational modulator of HER2 hyperactivation, which can lead to the intrinsic resistance to HER2-targeted therapy. SH3BGRL would be a pivotal therapy target and a diagnostic marker to HER2-positve patients. Thus, targeting SH3BGRL or the downstream signaling could relieve the innate resistance to some HER2-tageted therapies for both HER2 and SH3BGRL-postive breast cancers. |
topic |
SH3BGRL HER2 Breast cancer Drug resistance |
url |
http://link.springer.com/article/10.1186/s13046-020-01577-z |
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