The integrin alpha(v)beta(3-5) ligand MFG-E8 is a p63/p73 target gene in triple-negative breast cancers but exhibits suppressive functions in ER(+) and erbB2(+) breast cancers.
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.
Cancer Research Center at Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Chuanwei
C
Yang
Tetsu
T
Hayashida
Nicole
N
Forster
Cuiqi
C
Li
Dejun
D
Shen
Shyamala
S
Maheswaran
Li
L
Chen
Karen S
KS
Anderson
Leif W
LW
Ellisen
Dennis
D
Sgroi
Emmett V
EV
Schmidt
D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000378:metabolism*; D019030:Receptors, Vitronectin / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D000954:Antigens, Surface; D000970:Antineoplastic Agents; D002945:Cisplatin; D004268:DNA-Binding Proteins; D039302:Integrin alphaVbeta3; D008024:Ligands; D008565:Membrane Proteins; D008894:Milk Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D019030:Receptors, Vitronectin; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C081876:CKAP4 protein, human; C098942:MFGE8 protein, human; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; C064660:integrin alphaVbeta5