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Amplification and overexpression of peroxisome proliferator-activated receptor binding protein (PBP/PPARBP) gene in breast cancer.

Abstract
Peroxisome proliferator-activated receptor binding protein (PBP), a nuclear receptor coactivator, interacts with estrogen receptor alpha (ERalpha) in the absence of estrogen. This interaction was enhanced in the presence of estrogen but was reduced in the presence of antiestrogen, tamoxifen. Transfection of PBP in CV-1 cells resulted in enhancement of estrogen-dependent transcription, indicating that PBP serves as a coactivator in ER signaling. To examine whether overexpression of PBP plays a role in breast cancer because of its coactivator function in ER signaling, we determined the levels of PBP expression in breast tumors. High levels of PBP expression were detected in approximately 50% of primary breast cancers and breast cancer cell lines by ribonuclease protection analysis, in situ hybridization, and immunoperoxidase staining. Fluorescence in situ hybridization of human chromosomes revealed that the PBP gene is located on chromosome 17q12, a region that is amplified in some breast cancers. We found PBP gene amplification in approximately 24% (6/25) of breast tumors and approximately 30% (2/6) of breast cancer cell lines, implying that PBP gene overexpression can occur independent of gene amplification. This gene comprises 17 exons that, together, span >37 kilobases. The 5'-flanking region of 2.5 kilobase pairs inserted into a luciferase reporter vector revealed that the promoter activity in CV-1 cells increased by deletion of nucleotides from -2,500 to -273. The -273 to +1 region, which exhibited high promoter activity, contains a typical CCAT box and multiple cis-elements such as C/EBPbeta, YY1, c-Ets-1, AP1, AP2, and NFkappaB binding sites. These observations, in particular PBP gene amplification, suggest that PBP, by its ability to function as ERalpha coactivator, might play a role in mammary epithelial differentiation and in breast carcinogenesis.
AuthorsY Zhu, C Qi, S Jain, M M Le Beau, R Espinosa 3rd, G B Atkins, M A Lazar, A V Yeldandi, M S Rao, J K Reddy
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 96 Issue 19 Pg. 10848-53 (Sep 14 1999) ISSN: 0027-8424 [Print] United States
PMID10485914 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Carrier Proteins
  • Estrogen Receptor alpha
  • MED1 protein, human
  • Mediator Complex Subunit 1
  • RNA, Messenger
  • Receptors, Estrogen
  • Transcription Factors
Topics
  • Base Sequence
  • Breast Neoplasms (genetics, metabolism)
  • Carrier Proteins (genetics, metabolism)
  • Chromosomes, Human, Pair 17
  • Cloning, Molecular
  • Estrogen Receptor alpha
  • Exons
  • Humans
  • In Situ Hybridization, Fluorescence
  • Mediator Complex Subunit 1
  • Molecular Sequence Data
  • Plasmids
  • Promoter Regions, Genetic
  • RNA, Messenger (analysis)
  • Receptors, Estrogen (metabolism)
  • Transcription Factors
  • Transfection
  • Tumor Cells, Cultured

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