Transcriptional Control of the ERBB2 Amplicon by ERRα and PGC-1β Promotes Mammary Gland Tumorigenesis

Overexpression of ERBB2 and its neighboring genes on chromosome 17 occurs in approximately 25% of breast tumors and is associated with poor prognosis. While amplification of the 17q12-21 chromosomal region often correlates with an increase in the transcriptional rates of the locus, the molecular mechanisms and the factors involved in the coordinated expression of genes residing within the ERBB2 amplicon remain largely unknown. Here we demonstrate that estrogen-related receptor alpha (ERR alpha, NR3B1) and its coregulator PGC-1 beta are key effectors in this process. Using a mouse model of ERBB2-initiated mammary tumorigenesis, we first show that ablation of ERRa significantly delays ERBB2-induced tumor development and lowers the levels of amplicon transcripts. Chromosome 17q-wide binding site location analyses in human breast cancer cells show preferential recruitment of ERRa to DNA segments associated with the ERBB2 amplicon. Furthermore, ERR alpha directs the co-recruitment of the coactivator PGC-1 beta to segments in the 17q12 region and the recruitment of RNA polymerase II to the promoters of the ERBB2 and coamplified genes. ERR alpha and PGC-1 beta also participate in the de-repression of ERBB2 expression through competitive genomic cross-talk with estrogen receptor alpha (ER alpha) and, as a consequence, influence tamoxifen sensitivity in breast cancer cells. Taken together, our results suggest that ERR alpha and PGC-1 beta are key players in the etiology of malignant breast cancer by coordinating the transcriptional regulation of genes located in the 17q12 region, a process that also involves interference with the repressive function of ER alpha on ERBB2 expression. Cancer Res; 70(24); 10277-87. (C)2010 AACR.