title: MTDH mediates trastuzumab resistance in HER2 positive breast cancer by decreasing PTEN expression through an NFκB-dependent pathway.
abstract: 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.
authors.forename: Cheng
authors.initials: C
authors.lastname: Du
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Yi
authors.forename: Wenchao
authors.initials: W
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.forename: Zhaozhe
authors.initials: Z
authors.lastname: Liu
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ding
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Ying
authors.initials: Y
authors.lastname: Piao
authors.forename: Jianlin
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Oncology, General Hospital of Shenyang Military Area Command, Shenyang 110016, P, R, China. hylcardiology@163.com.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Han
authors.forename: Manjiang
authors.initials: M
authors.lastname: Xie
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xie
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D008354:Mannitol Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D008354:Mannitol Dehydrogenases; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C116789:mannitol 2-dehydrogenase (NADP); C494929:PTEN protein, human