BRCA1 suppresses osteopontin-mediated breast cancer.
BRCA1 is a well described breast cancer susceptibility gene thought to be involved primarily in DNA repair. However, mutation within the BRCA1 transcriptional domain is also implicated in neoplastic transformation of mammary epithelium, but responsible mechanisms are unclear. Here we show in a rat mammary model system that wild type (WT) BRCA1 specifically represses the expression of osteopontin (OPN), a multifunctional estrogen-responsive gene implicated in oncogenic transformation, particularly that of the breast. WT.BRCA1 selectively binds OPN-activating transcription factors estrogen receptor alpha, AP-1, and PEA3, inhibits OPN promoter transactivation, and suppresses OPN mRNA and protein both from an endogenous gene and a relevant model inducible gene. WT.BRCA1 also inhibits OPN-mediated neoplastic transformation characterized by morphology change, anchorage-independent growth, adhesion to fibronectin, and invasion through Matrigel. A mutant BRCA1 allele (Mut.BRCA1) associated with familial breast cancer lacks OPN suppressor effects, binds to WT.BRCA1, and impedes WT.BRCA1 suppression of OPN. Stable transfection of rat breast tumor cell lines with Mut.BRCA1 dramatically up-regulates OPN protein and induces anchorage independent growth. In human primary breast cancer, BRCA1 mutation is significantly associated with OPN overexpression. Taken together, these data suggest that BRCA1 mutation may confer increased tissue-specific cancer risk, in part by disruption of BRCA1 suppression of OPN gene transcription.
El-Tanani
Mohamed K
MK
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Grosvenor Road, Belfast BT12 6BJ, Northern Ireland, United Kingdom. m.el-tanani@qub.ac.uk
Campbell
Frederick Charles
FC
Crowe
Paul
P
Erwin
Pauline
P
Harkin
Denis Paul
DP
Pharoah
Paul
P
Ponder
Bruce
B
Rudland
Philip S
PS
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D019313:BRCA1 Protein; D047628:Estrogen Receptor alpha; D034741:RNA, Small Interfering; D014157:Transcription Factors; C065788:transcription factor PEA3; D053495:Osteopontin