Data from The Integrin α<sub>v</sub>β<sub>3-5</sub> Ligand MFG-E8 Is a p63/p73 Target Gene in Triple-Negative Breast Cancers but Exhibits Suppressive Functions in ER<sup>+</sup> and erbB2<sup>+</sup> Breast Cancers

Abstract

<div>Abstract<p>The progression from preinvasive lesion to invasive carcinoma is a critical step contributing to breast cancer lethality. We identified downregulation of milk fat globule-EGF factor 8 (MFG-E8) as a contributor to breast cancer progression using microarray analysis of laser capture microdissected (LCM) tissues. We first identified MFG-E8 downregulation in invasive lesions in transgenic mammary tumor models, which were confirmed in LCM-isolated human invasive ductal carcinomas compared with patient-matched normal tissues. <i>In situ</i> analyses of MFG-E8 expression in estrogen receptor (ER) positive cases confirmed its downregulation during breast cancer progression and small inhibitory MFG-E8 RNAs accelerated ER<sup>+</sup> breast cancer cell proliferation. MFG-E8 also decreased in erbB2<sup>+</sup> human cancers and erbB2 transgenic mice lacking MFG-E8 showed accelerated tumor formation. In contrast, MFG-E8 expression was present at high levels in triple-negative (ER<sup>−</sup>, PgR<sup>−</sup>, erbB2<sup>−</sup>) breast cancers, cell lines, and patient sera. Knockdown, chromatin immunoprecipitation, and reporter assays all showed that p63 regulates MFG-E8 expression, and MFG-E8 knockdowns sensitized triple-negative breast cancers to cisplatin treatment. Taken together, our results show that MFG-E8 is expressed in triple-negative breast cancers as a target gene of the p63 pathway, but may serve a suppressive function in ER<sup>+</sup> and erbB2<sup>+</sup> breast cancers. Its potential use as a serum biomarker that contributes to the pathogenesis of triple-negative breast cancers urges continued evaluation of its differential functions. <i>Cancer Res; 71(3); 937–45. ©2010 AACR</i>.</p></div>