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

Abstract

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 a (ERRa, NR3B1) and its coregulator PGC-1b 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, ERRa directs the corecruitment of the coactivator PGC-1b to segments in the 17q12 region and the recruitment of RNA polymerase II to the promoters of the ERBB2 and coamplified genes. ERRa and PGC-1b also participate in the de-repression of ERBB2 expression through competitive genomic cross-talk with estrogen receptor a (ERa) and, as a consequence, influence tamoxifen sensitivity in breast cancer cells. Taken together, our results suggest that ERRa and PGC-1b 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 ERa on ERBB2 expression.

β-Catenin Signaling Is a Critical Event in ErbB2-Mediated Mammary Tumor Progression

“…Although we could not detect recruitment of b-catenin to the ERBB2 proximal promoter, we detected a 3-fold enrichment in b-catenin and a 20-fold enrichment in RNA polymerase II recruitment to an intronic ERBB2 site (Fig. 7D), which has been shown to be bound by several factors that are important in the transcriptional regulation of ERBB2 (18,38). b-Catenin and RNA polymerase II occupancy to this site was further enriched upon treatment with the Wnt3 ligand (Fig.…”

“…We found recruitment of b-catenin and RNA polymerase II at an intronic ERBB2 site, which was further enhanced upon Wnt3 exposure, whereas ICG-001 treatment disrupted RNA polymerase II occupancy at this site. This site is particularly important as transcription factors such as ERRa and ER-a have been shown to compete for binding to this site to activate or repress ERBB2 transcription (18,38). In addition, recent data have established that ERRa, b-catenin, and Lef1 form a transcriptionally active complex to activate gene expression (53).…”

Emerging functional roles of nuclear receptors in breast cancer

“…All three ESRR isoforms were identified as coactivating Review t b doan and others Nuclear receptors in breast cancer factors of HIF and to enhance HIF-induced glycolytic and angiogenic gene expression in hypoxic condition (Ao et al 2008). ESRRA also regulates the expression of ERRB2 (Deblois et al 2010), which was reported to translocate to the mitochondria of tumor cells and regulate energy metabolism. Overexpression of mitochondrial ERBB2 decreases mitochondrial electron transport chain activity and enhances cellular glycolysis (Ding et al 2012).…”

PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism

“…This is consistent with recent findings that PGC1β promotes tumorigenesis in many tissues through the PGC1/ERR signaling axis (Deblois et al ., 2010, 2013; Eichner et al ., 2010). In this study, we show that LDHA is upregulated by the PGC1β/RXRβ signaling pathway and partly contributes to tumorigenesis.…”

“…Recent studies have shown that PGC1β is upregulated in cancer cells and promotes tumorigenesis by regulation of mitochondrial biogenesis and glycolysis metabolism (Bellafante et al ., 2014; Chang et al ., 2011; Deblois et al ., 2010; Deblois et al ., 2013), while the detailed mechanism still needs to be fully understood.…”