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Tumor Biology

, Volume 37, Issue 4, pp 5445–5454 | Cite as

Inhibition of autophagy induced by PTEN loss promotes intrinsic breast cancer resistance to trastuzumab therapy

  • Liao Ning
  • Zhang Guo-Chun
  • An Sheng-Li
  • Li Xue-Rui
  • Wang Kun
  • Zu Jian
  • Ren Chong-Yang
  • Wen Ling-Zhu
  • Lv Hai-Tong
Original Article

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.

Keywords

PTEN Autophagy Breast cancer Trastuzumab shRNA LC3I/II 

Notes

Acknowledgments

This work has been supported by two grants encoded as 81071851 and 81001189 from the National Natural Science Foundation of China, a grant encoded as S2011010001318 from Guangdong Natural Science Foundation, and a grant encoded as 2012A030400016 from Guangdong Provincial Department of Science and Technology.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Liao Ning
    • 1
  • Zhang Guo-Chun
    • 1
  • An Sheng-Li
    • 2
  • Li Xue-Rui
    • 1
  • Wang Kun
    • 1
  • Zu Jian
    • 1
  • Ren Chong-Yang
    • 1
  • Wen Ling-Zhu
    • 3
  • Lv Hai-Tong
    • 3
  1. 1.Department of Breast Cancer, Cancer CenterGuangdong General Hospital & Guangdong Academy of Medical SciencesGuangzhouChina
  2. 2.School of Public Health and Tropical MedicineSouthern Medical UniversityGuangzhouChina
  3. 3.Southern Medical UniversityGuangzhouChina

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