Decreased mitochondrial SIRT3 expression is a potential molecular biomarker associated with poor outcome in breast cancer.

SIRT3 is a genomically expressed, mitochondrial localized tumor suppressor protein where it directs multiple metabolic processes by deacetylating downstream protein substrates. Genetic deletion of Sirt3 in mice leads to the spontaneous development of mammary tumors starting at 1 year, and decreased SIRT3 messenger RNA has been observed in several human tumors including breast malignancies. In this investigation, we assessed SIRT3 expression in human breast cancer tissue microarray and examined the relationship between SIRT3 expression and outcome in patients with breast cancer. SIRT3 protein expression is significantly lower in neoplastic compared with normal breast epithelium, including normal epithelium adjacent to tumors. Patients with breast cancer in the lowest quartile of SIRT3 expression had a significantly shorter locoregional relapse-free survival (hazard ratio, 0.53 [0.47-0.61]; log-rank P = 0). Notably, low SIRT3 expression was associated with reduced locoregional relapse-free survival in all breast cancer subtypes analyzed, including ER+, ER-, HER2+, and basal subtypes (hazard ratios, 0.44-0.65; log-rank P = 0-.0019). These results highlight the importance of the SIRT3 as a tumor suppressor protein in breast cancer and suggest that SIRT3 may be a potential molecular biomarker to identify high-risk patients across all molecular subtypes of breast cancer.

Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis.

Cooperativity between oncogenic mutations is recognized as a fundamental feature of malignant transformation, and it may be mediated by synergistic regulation of the expression of pro- and antitumorigenic target genes. However, the mechanisms by which oncogenes and tumor suppressors coregulate downstream targets and pathways remain largely unknown. Here, we used ChIP coupled to massively parallel sequencing (ChIP-seq) and gene expression profiling in mouse prostates to identify direct targets of the tumor suppressor Nkx3.1. Further analysis indicated that a substantial fraction of Nkx3.1 target genes are also direct targets of the oncoprotein Myc. We also showed that Nkx3.1 and Myc bound to and crossregulated shared target genes in mouse and human prostate epithelial cells and that Nkx3.1 could oppose the transcriptional activity of Myc. Furthermore, loss of Nkx3.1 cooperated with concurrent overexpression of Myc to promote prostate cancer in transgenic mice. In human prostate cancer patients, dysregulation of shared NKX3.1/MYC target genes was associated with disease relapse. Our results indicate that NKX3.1 and MYC coregulate prostate tumorigenesis by converging on, and crossregulating, a common set of target genes. We propose that coregulation of target gene expression by oncogenic/tumor suppressor transcription factors may represent a general mechanism underlying the cooperativity of oncogenic mutations during tumorigenesis.