Selective activation of trophoblast-specific PLAC1 in breast cancer by CCAAT/enhancer-binding protein beta (C/EBPbeta) isoform 2.
The trophoblast-specific gene PLAC1 (placenta-specific 1) is ectopically expressed in a wide range of human malignancies, most frequently in breast cancer, and is essentially involved in cancer cell proliferation, migration, and invasion. Here we show that basal activity of the PLAC1 promoter is selectively controlled by ubiquitous transcription factor SP1 and isoform 2 of CCAAT/enhancer-binding protein beta that we found to be selectively expressed in placental tissue and cancer cells. Binding of both factors to their respective elements within the PLAC1 promoter was essential to attain full promoter activity. Estrogen receptor alpha (ERalpha) signaling further augmented transcription and translation of PLAC1 and most likely accounts for the positive correlation between PLAC1 expression levels and the ERalpha status we observed in primary breast cancer specimens. DNA affinity precipitation and chromatin immunoprecipitation assays revealed that transactivation of the PLAC1 promoter by ligand-activated ERalpha is based on a nonclassical pathway independent of estrogen-response elements, by tethering of ERalpha to DNA-bound CCAAT/enhancer-binding protein beta-2, and SP1. Our findings provide first insight into a novel and hitherto unknown regulatory mechanism governing selective activation of trophoblast-specific gene expression in breast cancer.
Koslowski
Michael
M
Department of Internal Medicine III, Experimental and Translational Oncology, Johannes Gutenberg University, 55131 Mainz, Germany.
Türeci
Ozlem
O
Biesterfeld
Stefan
S
Seitz
Gerhard
G
Huber
Christoph
C
Sahin
Ugur
U
D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D011257:Pregnancy Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism*
D022782:CCAAT-Enhancer-Binding Protein-beta; D047628:Estrogen Receptor alpha; D004967:Estrogens; C415583:PLAC1 protein, human; D011257:Pregnancy Proteins; D020033:Protein Isoforms; D016329:Sp1 Transcription Factor