GRB7 dependent proliferation of basal‐like, HER‐2 positive human breast cancer cell lines is mediated in part by HER‐1 signaling
| Autor: | Wendy Wagoner, Koei Chin, Xiaoyan Wang, Elizabeth Ramsey, Shiuh Wen Luoh, Xinhe Lai, Zhi Hu, Rosalie Sears |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Receptor ErbB-2 medicine.medical_treatment Apoptosis Breast Neoplasms Mice SCID Lapatinib Article Targeted therapy Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Movement Mice Inbred NOD Tumor Cells Cultured medicine Animals Humans Phosphorylation Molecular Biology Cell Proliferation Neoplasms Basal Cell biology GRB7 Tyrosine phosphorylation Transfection Xenograft Model Antitumor Assays ErbB Receptors 030104 developmental biology chemistry Cell culture GRB7 Adaptor Protein 030220 oncology & carcinogenesis biology.protein Cancer research Female Signal transduction Signal Transduction medicine.drug |
| Zdroj: | Molecular Carcinogenesis. 58:699-707 |
| ISSN: | 1098-2744 0899-1987 |
| DOI: | 10.1002/mc.22963 |
| Popis: | GRB7 gene encodes a multi-domain signal transduction molecule and is part of the core of the HER-2 amplicon. GRB7 is commonly co-amplified and overexpressed with HER-2 in human breast cancer. This study addresses the role of GRB7 in HER-2 positive human breast cancers resistant to HER-2 targeted therapy. HCC1954, 21MT1, and JIMT1 are basal like HER-2 positive breast cancer cell lines based on expression profiling. These three cell lines are resistant to trastuzumab and lapatinib treatment. Knockdown of GRB7 protein expression with siRNA transfection as well as lentiviral vector mediated shRNA over-expression decreased the growth of HCC1954, 21MT1, and JIMT1 cells in vitro and the growth of tumor xenografts these cells formed in animal models. When assayed by ki-67 staining and TUNEL assay, the mechanism of reduced tumor xenograft growth appeared to be distinct. Reduced proliferation and increased apoptosis were seen in 21MT1 cells, while reduced proliferation was seen in HCC1954 cells and increased apoptosis in JIMT1 cells. Phospho-proteome profiling found HER-1 tyrosine phosphorylation was reduced with GRB7 knock down in JIMT1 cells. Immuno-blotting and immuno-precipitation experiments found HER-1 phosphorylation was reduced with GRB7 knock down in all three cell lines. HER-1 knock down via siRNA transient transfection as well as blocking HER-1 function with panitumumab decreased proliferation of all three cell lines in vitro. Our study finds that GRB7 has an essential growth promoting function which is mediated in part by HER-1 activation. The potential of HER-1 targeting in therapy resistant HER-2 positive breast cancer merits further study. |
| Databáze: | OpenAIRE |
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