The integrin αvβ3-5 ligand MFG-E8 is a p63/p73 target gene in triple-negative breast cancers but exhibits suppressive functions in ER+ and erbB2+ breast cancers

Chuanwei Yang, Tetsu Hayashida, Nicole Forster, Cuiqi Li, Dejun Shen, Shyamala Maheswaran, Li Chen, Karen S. Anderson, Leif W. Ellisen, Dennis Sgroi, Emmett V. Schmidt

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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. In situ 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+ breast cancer cell proliferation. MFG-E8 also decreased in erbB2+ 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-, PgR-, erbB2-) 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+ and erbB2+ 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.

Original languageEnglish
Pages (from-to)937-945
Number of pages9
JournalCancer Research
Volume71
Issue number3
DOIs
Publication statusPublished - 2011 Feb 1
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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