1. Inhibition of autophagy induced by PTEN loss promotes intrinsic breast cancer resistance to trastuzumab therapy.
- Author
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Ning L, Guo-Chun Z, Sheng-Li A, Xue-Rui L, Kun W, Jian Z, Chong-Yang R, Ling-Zhu W, and Hai-Tong L
- Subjects
- Animals, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Microtubule-Associated Proteins genetics, RNA-Binding Proteins biosynthesis, Receptor, ErbB-2 genetics, Signal Transduction, TOR Serine-Threonine Kinases biosynthesis, Trastuzumab administration & dosage, Xenograft Model Antitumor Assays, Autophagy drug effects, Breast Neoplasms drug therapy, Microtubule-Associated Proteins biosynthesis, PTEN Phosphohydrolase genetics
- Abstract
This study aims to explore the effects of the phosphatase and tension homolog (PTEN) expression level on autophagic status and on the resistance of breast cancer to trastuzumab treatment. PTEN and LC3I/II were knocked down with shRNA expression vectors, which were transfected into estrogen receptor (ER)-positive breast cancer cell lines. After trastuzumab treatment, the changes in the autophagy signal transduction pathways and autophagic proteins (LC3I/II, p62, LAMP, and cathepsin B) in these stably transfected cells were detected using western blot. The cells were also orthotopically implanted into nude mice to explore the influence of PTEN knockdown on tumor size, cell viability, and autophagic proteins after trastuzumab treatment. Similar determinations were performed using the LC3I/II overexpressed shPTEN breast cancer cells (LC3I/II-shPTEN). Downregulation of PTEN and autophagic proteins LC3-I and LC3-II was observed in resistant human breast cancer samples. Knockdown of PTEN and PTEN+ LC3I/II with shRNA in breast cancer cells resulted in increased resistance to trastuzumab. Consistently, trastuzumab treatment could not effectively reduce tumor size. Significant decreases in the levels of autophagic proteins LC3I/II, LAMP, p62, cathepsin B, and PI3K-Akt-mTOR and the signaling pathway protein Akt were found in PTEN knockdown cells, compared to the PTEN normal group, after trastuzumab administration, both in vitro and in vivo. However, these findings were reversed with the LC3I/II-shPTEN treatment. Therefore, the loss of PTEN may promote the development of primary resistance to trastuzumab in breast cancer via autophagy defects.
- Published
- 2016
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