Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Mahnaz Janghorban, Amy S. Farrell, Brittany L. Allen-Petersen, Carl Pelz, Colin J. Daniel, Jessica Oddo, Ellen M. Langer, Dale J. Christensen, Rosalie C. Sears

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor- 2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types. Here we show that SET is overexpressed in about 50-60% and CIP2A in about 90% of breast cancers. Knockdown of SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells in vitro or in vivo with OP449, a novel SET antagonist, also decreases the tumorigenic potential of breast cancer cells and induces apoptosis. We show that this is, at least in part, due to decreased S62 phosphorylation of c-MYC and reduced c-MYC activity and target gene expression. Because of the ubiquitous expression and tumor suppressor activity of PP2A in cells, as well as the critical role of c-MYC in human cancer, we propose that activation of PP2A (here accomplished through antagonizing endogenous inhibitors) could be a novel antitumor strategy to posttranslationally target c-MYC in breast cancer.

Original languageEnglish (US)
Pages (from-to)9157-9162
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number25
DOIs
StatePublished - Jun 24 2014

Keywords

  • Breast cancer therapy
  • Phosphatase activator

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer'. Together they form a unique fingerprint.

  • Cite this