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

Peroxisome proliferator-activated receptor binding protein (PBP), a nuclear receptor coactivator, interacts with estrogen receptor alpha (ER alpha) in the absence of estrogen. This interaction was enhanced in the presence of estrogen but was reduced in the presence of antiestrogen, tamoxifen. Transf ection of PBP in CV-I cells resulted in enhancement of estrogen-dependent t ranscription, indicating that PBP serves as a coactivator in ER signaling. To examine whether overexpression of PBP plays a role in breast cancer beca use of its coactivator function in ER signaling, we determined the levels o f PBP expression in breast tumors. High levels of PBP expression were detec ted in approximate to 50% of primary breast cancers and breast cancer cell lines by ribonuclease protection analysis, in situ hybridization, and immun operoxidase staining. Fluorescence in situ hybridization of human chromosom es 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 ap proximate to 24% (6/25) of breast tumors and approximate to 30% (2/6) of br east cancer cell lines, Implying that PBP gene overexpression can occur ind ependent 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 C V-I cells increased by deletion of nucleotides from -2,500 to -273. The -27 3 to +1 region, which exhibited high promoter activity, contains a typical CCAT box and multiple cis-elements such as C/EBP beta, Wi, c-Ets-l, AP1, AP 2, and NF kappa B binding sites. These observations, in particular PBP gene amplification, suggest that PBP, by its ability to function as ER alpha co activator, might play a role in mammary epithelial differentiation and in b reast carcinogenesis.