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

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Tumor Biology

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.

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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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Authors and Affiliations

  1. Department of Breast Cancer, Cancer Center, Guangdong General Hospital & Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, 510080, Guangzhou, Guangdong, China

    Liao Ning, Zhang Guo-Chun, Li Xue-Rui, Wang Kun, Zu Jian & Ren Chong-Yang

  2. School of Public Health and Tropical Medicine, Southern Medical University, 510080, Guangzhou, Guangdong, China

    An Sheng-Li

  3. Southern Medical University, 510080, Guangzhou, Guangdong, China

    Wen Ling-Zhu & Lv Hai-Tong

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  1. Liao Ning
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  2. Zhang Guo-Chun
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  3. An Sheng-Li
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  4. Li Xue-Rui
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  5. Wang Kun
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Correspondence to Liao Ning.

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Ning, L., Guo-Chun, Z., Sheng-Li, A. et al. Inhibition of autophagy induced by PTEN loss promotes intrinsic breast cancer resistance to trastuzumab therapy. Tumor Biol. 37, 5445–5454 (2016). https://doi.org/10.1007/s13277-015-4392-0

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  • DOI: https://doi.org/10.1007/s13277-015-4392-0

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