BRCA1-IRIS regulates cyclin D1 expression in breast cancer cells

• Published in: Experimental cell research 2006-10, Vol.312 (16), p.3120-3131
• Main Authors: Nakuci, Enkeleda, Mahner, Sven, DiRenzo, James, ElShamy, Wael M.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; BRCA1 Protein - metabolism; BRCA1-IRIS; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; c-Jun; CARCINOMAS; CELL CYCLE; CELL PROLIFERATION; Chromosomal Proteins, Non-Histone - metabolism; Cyclin D1; Cyclin D1 - genetics; Cyclin D1 - metabolism; Enzyme Activation; Estrogen Receptor alpha - metabolism; Exons - genetics; Gene expression; Gene Silencing; GENES; Humans; JNK; JNK Mitogen-Activated Protein Kinases - metabolism; MAMMARY GLANDS; Promoter Regions, Genetic - genetics; PROMOTERS; Protein Binding; Proto-Oncogene Proteins c-jun - metabolism; Proto-Oncogene Proteins c-myc - metabolism; RECEPTORS; Signal transduction; SRC1; SRC3; Trans-Activators - metabolism; Transcription Factor AP-1 - metabolism; Transcription, Genetic; Transcriptional Activation - genetics; TUMOR CELLS; Tumor Cells, Cultured; Tumors
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2006.06.021

The regulator of cell cycle progression, cyclin D1, is up-regulated in breast cancer cells; its expression is, in part, dependent on ERα signaling. However, many ERα-negative tumors and tumor cell lines (e.g., SKBR3) also show over-expression of cyclin D1. This suggests that, in addition to ERα signaling, cyclin D1 expression is under the control of other signaling pathways; these pathways may even be over-expressed in the ERα-negative cells. We previously noticed that both ERα-positive and -negative cell lines over-express BRCA1-IRIS mRNA and protein. Furthermore, the level of over-expression of BRCA1-IRIS in ERα-negative cell lines even exceeded its over-expression level in ERα-positive cell lines. In this study, we show that: (1) BRCA1-IRIS forms complex with two of the nuclear receptor co-activators, namely, SRC1 and SRC3 (AIB1) in an ERα-independent manner. (2) BRCA1-IRIS alone, or in connection with co-activators, is recruited to the cyclin D1 promoter through its binding to c-Jun/AP1 complex; this binding activates the cyclin D1 expression. (3) Over-expression of BRCA1-IRIS in breast cells over-activates JNK/c-Jun; this leads to the induction of cyclin D1 expression and cellular proliferation. (4) BRCA1-IRIS activation of JNK/c-Jun/AP1 appears to account for this, because in cells that were depleted from BRCA1-IRIS, JNK remained inactive. However, depletion of SRC1 or SRC3 instead reduced c-Jun expression. Our data suggest that this novel signaling pathway links BRCA1-IRIS to cellular proliferation through c-Jun/AP1 nuclear pathway; finally, this culminates in the increased expression of the cyclin D1 gene.