MTDH mediates trastuzumab resistance in HER2 positive breast cancer by decreasing PTEN expression through an NFκB-dependent pathway

BMC Cancer

Cheng Du²  Xiaomin Yi³  Wenchao Liu²  Tao Han⁴  Zhaozhe Liu⁴  Zhenyu Ding⁴  Zhendong Zheng⁴  Ying Piao⁴  Jianlin Yuan⁵  Yaling Han¹  Manjiang Xie⁶  Xiaodong Xie⁴ 

[1] Department of Cardiology, General Hospital of Shenyang Military Area Command, Shenyang 110016, P. R. China

[2] Department of Oncology, Xijing Hospital, Fourth Military Medical University, Xi’an, P. R. China

[3] Department of Urology, PLA 105 Hospital, Hefei, P. R. China

[4] Department of Oncology, General Hospital of Shenyang Military Area Command, Shenyang 110016, P. R. China

[5] Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, P. R. China

[6] Key Laboratory of Aerospace Medicine, Ministry of Education, Fourth Military Medical University, Xi’an 710032, P. R. China

关键词: Nuclear factor kappa B (NFκB);    Phosphatase and tensin homologue deleted from chromosome 10 (PTEN);    Breast cancer;    Human epidermal growth factor receptor 2 (HER2);    Drug resistance;    Trastuzumab;    Metadherin (MTDH);   

Others  :  1118016
DOI  :  10.1186/1471-2407-14-869

 received in 2014-07-11, accepted in 2014-11-14,  发布年份 2014

【 摘 要 】

Background

Trastuzumab resistance is almost inevitable in the management of human epidermal growth factor receptor (HER) 2 positive breast cancer, in which phosphatase and tensin homolog deleted from chromosome 10 (PTEN) loss is implicated. Since metadherin (MTDH) promotes malignant phenotype of breast cancer, we sought to define whether MTDH promotes trastuzumab resistance by decreasing PTEN expression through an NFκB-dependent pathway.

Methods

The correlations between MTDH and PTEN expressions were analyzed both in HER2 positive breast cancer tissues and trastuzumab resistant SK-BR-3 (SK-BR-3/R) cells. Gene manipulations of MTDH and PTEN levels by knockdown or overexpression were utilized to elucidate molecular mechanisms of MTDH and PTEN implication in trastuzumab resistance. For in vivo studies, SK-BR-3 and SK-BR-3/R cells and modified derivatives were inoculated into nude mice alone or under trastuzumab exposure. Tumor volumes, histological examinations as well as Ki67 and PTEN expressions were revealed.

Results

Elevated MTDH expression indicated poor clinical benefit, shortened progression free survival time, and was negatively correlated with PTEN level both in HER2 positive breast cancer patients and SK-BR-3/R cells. MTDH knockdown restored PTEN expression and trastuzumab sensitivity in SK-BR-3/R cells, while MTDH overexpression prevented SK-BR-3 cell death under trastuzumab exposure, probably through IκBα inhibition and nuclear translocation of p65 which subsequently decreased PTEN expression. Synergized effect of PTEN regulation were observed upon MTDH and p65 co-transfection. Forced PTEN expression in SK-BR-3/R cells restored trastuzumab sensitivity. Furthermore, decreased tumor volume and Ki67 level as well as increased PTEN expression were observed after MTDH knockdown in subcutaneous breast cancer xenografts from SK-BR-3/R cells, while the opposite effect were found in grafts from MTDH overexpressing SK-BR-3 cells.

Conclusions

MTDH overexpression confers trastuzumab resistance in HER2 positive breast cancer. MTDH mediates trastuzumab resistance, at least in part, by PTEN inhibition through an NFκB-dependent pathway, which may be utilized as a promising therapeutic target for HER2 positive breast cancer.

【 授权许可】

   
2014 Du et al.; licensee BioMed Central Ltd.

【 图 表 】

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