Pnck overexpression in HER-2 gene-amplified breast cancer causes Trastuzumab resistance through a paradoxical PTEN-mediated process

Tushar B. Deb, Annie H. Zuo, Robert J. Barndt, Surojeet Sengupta, Radmila Jankovic, Michael D. Johnson

Research output: Contribution to journalArticlepeer-review

Abstract

The gene for Pregnancy Up-regulated Non-ubiquitous Calmodulin Kinase (Pnck), a novel calmodulin kinase, is expressed in roughly one-third of human breast tumors, but not in adjoining normal tissues. Pnck alters EGFR stability and function, prompting this study to determine if Pnck expression has implications for HER-2 function and HER-2-directed therapy. The frequency of Pnck expression in HER-2-amplified breast cancer was examined by immunohistochemistry, and the impact of Pnck expression in the presence of HER-2 amplification on cancer cell proliferation, clonogenicity, cell-cycle progression, and Trastuzumab sensitivity was examined in vitro by transfection of cells with Pnck. Cell signaling was probed by Western blot analysis and shRNA-mediated PTEN knockdown. Over 30 % of HER-2 amplified tumors were found to express Pnck. Expression of Pnck in SkBr3 cells resulted in increased proliferation, clonal growth, cell-cycle progression, and Trastuzumab resistance. Pnck expression increases Hsp27 expression, Trastuzumab partial agonist activity on HER-2 Y1248 phosphorylation, and suppressed extracellular signal-regulated kinase (ERK1/2) activity. Knockdown of endogenous PTEN upregulated ERK1/2 activity, inhibited cellular proliferation, and partially sensitized Pnck/SKBr3 cells to Trastuzumab treatment. Increased proliferation of the Pnck/SKBr3 cells was observed following expression of protein phosphatase active and lipid phosphatase dead PTEN mutant but not the total phosphatase dead PTEN mutant. Co-overexpression of HER-2 and Pnck results in enhanced tumor cell proliferation and Trastuzumab resistance that is paradoxically dependent on PTEN protein phosphatase activity. This suggests that Pnck may be a marker of Trastuzumab resistance and possibly a therapeutic target.

Original languageEnglish (US)
Pages (from-to)347-361
Number of pages15
JournalBreast Cancer Research and Treatment
Volume150
Issue number2
DOIs
StatePublished - Apr 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015, Springer Science+Business Media New York.

Keywords

  • ERK1/2
  • HER-2
  • PTEN
  • Pnck
  • Trastuzumab

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