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

31 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

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Triple Negative Breast Neoplasms
Epidermal Growth Factor
Integrins
Estrogen Receptors
Breast Neoplasms
Ligands
Genes
Down-Regulation
Lasers
milk fat globule
Ductal Carcinoma
Chromatin Immunoprecipitation
Microarray Analysis
Serum
Cisplatin
Transgenic Mice
Neoplasms
Biomarkers
Cell Proliferation
RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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

In: Cancer Research, Vol. 71, No. 3, 01.02.2011, p. 937-945.

Research output: Contribution to journalArticle

Yang, Chuanwei ; Hayashida, Tetsu ; Forster, Nicole ; Li, Cuiqi ; Shen, Dejun ; Maheswaran, Shyamala ; Chen, Li ; Anderson, Karen S. ; Ellisen, Leif W. ; Sgroi, Dennis ; Schmidt, Emmett V. / 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. In: Cancer Research. 2011 ; Vol. 71, No. 3. pp. 937-945.
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AU - Hayashida, Tetsu

AU - Forster, Nicole

AU - Li, Cuiqi

AU - Shen, Dejun

AU - Maheswaran, Shyamala

AU - Chen, Li

AU - Anderson, Karen S.

AU - Ellisen, Leif W.

AU - Sgroi, Dennis

AU - Schmidt, Emmett V.

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