Abstract
BackgroundTrastuzumab 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.MethodsThe 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.ResultsElevated 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.ConclusionsMTDH 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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-869) contains supplementary material, which is available to authorized users.
Highlights
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
PTEN dephosphorylates the 3’-sites of the phosphoinositides PIP2 and PIP3 that involve in the activation of PI3K/Protein kinase B (Akt) pathway, playing an important role in cellular survival
There were varied MTDH expressions in patient subgroups classified by positive nodal status (P = 0.026), advanced pathological stage (P = 0.012) and high Ki67 index (P = 0.033); there was no association between MTDH expression and age, hormone receptor status, or histological grade
Summary
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. HER2 overexpression in cancer cells promotes a malignant phenotype, presented as increased proliferation and invasion, reduced apoptosis, accelerated angiogenesis and enhanced resistance to anticancer therapy [2,3]. In approximately 20% of invasive breast cancer patients, HER2 overexpression occurs and correlates with shortened disease free survival and overall survival [4,5]. About 15% of patients with early-stage HER2 positive breast cancer progress to metastatic disease. Despite several mechanisms of trastuzumab resistance have been proposed, including loss of PTEN activity and upregulation of the PI3K/Akt pathway, accumulation of a truncated form of the HER2 receptor (p95-HER2), failure to elicit an appropriate immune response and increased signaling from alternative pathways such as EGFR and IGF-1R [10,11], the detailed mechanism implicated in trastuzumab resistance remains unclear
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