Enhancement of BRCA1 gene expression by the peroxisome proliferator-activated receptor gamma in the MCF-7 breast cancer cell line.
BRCA1 has been linked to the genetic susceptibility of a majority of familial breast and ovarian cancers. Several lines of evidence indicate that BRCA1 is a tumor suppressor and its expression is downregulated in sporadic breast and ovarian cancer cases. Therefore, the identification of genes involved in the regulation of BRCA1 gene expression might lead to new insights into the pathogenesis and treatment of these tumors. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily that has well-established roles in the regulation of adipocyte development and glucose homeostasis. More recently, it has been shown that ligands of PPARgamma have a potent antitumorigenic activity in breast cancer cells. In the present study we have found that two distinct ligands of PPARgamma; 15-deoxy-delta-(12,14)-prostaglandin J2 (15dPG-J2) and rosiglitazone, increase the levels of BRCA1 protein in human MCF-7 breast cancer cells. Immunofluorescence microscopy analysis showed that, after treatment with 15dPG-J2, the BRCA1 protein is mainly localized in the nucleus. Functional analysis by transient transfection of different 5'-flanking region fragments, as well as gel mobility shift assays and mutagenic analysis, suggests that the effects of 15dPG-J2 and rosiglitazone are mediated through a functional DR1 located between the nucleotides -241 and -229, which is a canonical PPARgamma type response element. Our data suggest that PPARgamma is a crucial gene regulating BRCA1 gene expression and might therefore be important for the BRCA1 regulatory pathway involved in the pathogenesis of sporadic breast and ovarian cancer.
Pignatelli
Miguel
M
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Spain.
Cocca
Claudia
C
Santos
Angel
A
Perez-Castillo
Ana
A
D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000378:metabolism; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*
D019313:BRCA1 Protein; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone