Breast cancer metastasis suppressor 1 (BRMS1) inhibits osteopontin transcription by abrogating NF-kappaB activation.
BACKGROUND
Osteopontin (OPN), a secreted phosphoglycoprotein, has been strongly associated with tumor progression and aggressive cancers. MDA-MB-435 cells secrete very high levels of OPN. However metastasis-suppressed MDA-MB-435 cells, which were transfected with breast cancer metastasis suppressor 1 (BRMS1), expressed significantly less OPN. BRMS1 is a member of mSin3-HDAC transcription co-repressor complex and has been shown to suppress the metastasis of breast cancer and melanoma cells in animal models. Hence we hypothesized that BRMS1 regulates OPN expression.


RESULTS
The search for a BRMS1-regulated site on the OPN promoter, using luciferase reporter assays of the promoter deletions, identified a novel NF-kappaB site (OPN/NF-kappaB). Electrophoretic mobility shift assays and chromatin immunoprecipitations (ChIP) confirmed this site to be an NF-kappaB-binding site. We also show a role of HDAC3 in suppression of OPN via OPN/NF-kappaB.


CONCLUSIONS
Our results show that BRMS1 regulates OPN transcription by abrogating NF-kappaB activation. Thus, we identify OPN, a tumor-metastasis activator, as a crucial downstream target of BRMS1. Suppression of OPN may be one of the possible underlying mechanisms of BRMS1-dependent suppression of tumor metastasis.
Samant
Rajeev S
RS
Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA. rsamant@usouthal.edu
Clark
David W
DW
Fillmore
Rebecca A
RA
Cicek
Muzaffer
M
Metge
Brandon J
BJ
Chandramouli
Kondethimmana H
KH
Chambers
Ann F
AF
Casey
Graham
G
Welch
Danny R
DR
Shevde
Lalita A
LA
D000107:Acetylation; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005260:Female; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins; D053495:Osteopontin / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D000099186:Histone Deacetylase 3
D006655:Histone Deacetylases; D016328:NF-kappa B; D009363:Neoplasm Proteins; D053495:Osteopontin; D011994:Recombinant Proteins; D012097:Repressor Proteins; D051996:Transcription Factor RelA; D000099186:Histone Deacetylase 3; C410024:BRMS1 protein, human