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

Breast Cancer Research and Treatment
Tushar B DebMichael D Johnson

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 prolifer...Continue Reading

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Citations

Oct 25, 2016·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Vahideh AlinejadMehdi Yousefi
Jul 13, 2016·Endocrine-related Cancer·Maria Theresa E MontalesRosalia C M Simmen
Apr 11, 2019·Cancers·David Jérémie BirnbaumEmilie Mamessier
Apr 22, 2017·Oncotarget·Mengyuan LiXiaosheng Wang

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