Data from The Ras/Mitogen-Activated Protein Kinase Pathway Inhibitor and Likely Tumor Suppressor Proteins, Sprouty 1 and Sprouty 2 Are Deregulated in Breast Cancer

Abstract

<div>Abstract<p>Sprouty (Spry) proteins were found to be endogenous inhibitors of the Ras/mitogen-activated protein kinase pathway that play an important role in the remodeling of branching tissues. We investigated <i>Spry</i> expression levels in various cancers and found that <i>Spry1</i> and <i>Spry2</i> were down-regulated consistently in breast cancers. Such prevalent patterns of down-regulation may herald the later application of these isoforms as tumor markers that are breast cancer specific and more profound than currently characterized markers. <i>Spry1</i> and <i>2</i> were expressed specifically in the luminal epithelial cells of breast ducts, with higher expression during stages of tissue remodeling when the epithelial ducts are forming and branching. These findings suggest that Sprys might be involved as a modeling counterbalance and surveillance against inappropriate epithelial expansion. The abrogation of endogenous Spry activity in MCF-7 cells by the overexpression of a previously characterized dominant-negative mutant of Spry, hSpry2<sup>Y55F</sup> resulted in enhanced cell proliferation <i>in vitro</i>. The hSpry2<sup>Y55F</sup> stably expressing cells also formed larger and greater number of colonies in the soft-agar assay. An <i>in vivo</i> nude mice assay showed a dramatic increase in the tumorigenic potential of hSpry2<sup>Y55F</sup> stable cells. The consistent down-regulation of <i>Spry1</i> and <i>2</i> in breast cancer and the experimental evidence using a dominant-negative hSpry2<sup>Y55F</sup> indicate that Spry proteins may actively maintain tissue integrity that runs amok when their expression is decreased below normal threshold levels. This alludes to a previously unrecognized role for Sprys in cancer development.</p></div>