title: Inhibition of autophagy induced by PTEN loss promotes intrinsic breast cancer resistance to trastuzumab therapy.
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.
authors.affiliation: Department of Breast Cancer, Cancer Center, Guangdong General Hospital & Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, 510080, Guangzhou, Guangdong, China. Drliao_ning@hotmail.com.
authors.forename: Liao
authors.initials: L
authors.lastname: Ning
authors.affiliation: Department of Breast Cancer, Cancer Center, Guangdong General Hospital & Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, 510080, Guangzhou, Guangdong, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Guo-Chun
authors.affiliation: School of Public Health and Tropical Medicine, Southern Medical University, 510080, Guangzhou, Guangdong, China.
authors.forename: An
authors.initials: A
authors.lastname: Sheng-Li
authors.affiliation: Department of Breast Cancer, Cancer Center, Guangdong General Hospital & Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, 510080, Guangzhou, Guangdong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xue-Rui
authors.affiliation: Department of Breast Cancer, Cancer Center, Guangdong General Hospital & Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, 510080, Guangzhou, Guangdong, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Kun
authors.affiliation: Department of Breast Cancer, Cancer Center, Guangdong General Hospital & Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, 510080, Guangzhou, Guangdong, China.
authors.forename: Zu
authors.initials: Z
authors.lastname: Jian
authors.affiliation: Department of Breast Cancer, Cancer Center, Guangdong General Hospital & Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, 510080, Guangzhou, Guangdong, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Chong-Yang
authors.affiliation: Southern Medical University, 510080, Guangzhou, Guangdong, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Ling-Zhu
authors.affiliation: Southern Medical University, 510080, Guangzhou, Guangdong, China.
authors.forename: Lv
authors.initials: L
authors.lastname: Hai-Tong
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis; D000068878:Trastuzumab / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D008869:Microtubule-Associated Proteins; D051059:PTEN Phosphohydrolase; D016601:RNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab; C477012:MAP1LC3A protein, human; C118585:P62 protein, human; C546842:MTOR protein, human; C494929:PTEN protein, human
keywords: Autophagy; Breast cancer; LC3I/II; PTEN; Trastuzumab; shRNA