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

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.

journal_name

Breast Cancer Res Treat

journal_title

Breast cancer research and treatment

authors

Deb TB,Zuo AH,Barndt RJ,Sengupta S,Jankovic R,Johnson MD

doi

10.1007/s10549-015-3337-z

subject

Has Abstract

pub_date

2015-04-01 00:00:00

pages

347-61

issue

eissn

0167-6806

issn

1573-7217

journal_volume

150

pub_type

杂志文章

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