Ivo results presented above suggest that the combination of high RR6 structure expression of Myc and JMJD6 might be associated with a poor clinical prognosis. To determine whether this might be true for human breast cancers, we performed an in silico analysis using the METABRIC database that contains microarray data and clinical information on about 2000 breast cancer patients. All cases were divided into four subsets, consisting of high/low, high/high, low/high, and low/low of JMJD6/Myc expression. When we compared patients with high versus low JMJD6 expression, we observed a highly significant effect in samples with high Myc rather than low Myc expression (compare p values for left and right panels in Fig. 10a, c). We determined that high JMJD6 expression is associated with a poor prognosis for ER-positive breast cancer patients and not for ERnegative breast cancer (Fig. 10b), consistent with a previous report analyzing JMJD6 expression as a biomarker for poor prognosis in ER+ breast cancer [25]. Overall, this analysis predicts PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27488460 that JMJD6 gene expression may be a discriminating factor for survival of patients with high Myc expression in ER-positive breast cancer patients.CFig. 10 High expression of JMJD6 and Myc shows the worst prognosis for human mammary gland tumors. a Kaplan-Meier survival curves are shown for the high versus low expression of JMJD6 in the presence of low (left panel) or high (right panel) expression of Myc. METABRIC database ( 2000 patients) was used to perform this analysis. Analysis was performed as in a for b ER-negative or c ER-positive mammary gland tumorsDiscussion Our array CNV results of 8 GEM models of mammary cancer demonstrated that there are common genomic amplifications and losses in multiple models as well as alterations that are more pronounced in specific models. These data, consistent with prior reports, demonstrates that the evolution of genomic alterations during tumorigenesis in these models appears to depend upon the genetic event that initiates transformation. We focused on the MMTV-Myc model since Myc is overexpressed in about 30 of human breast cancers and this model displays relatively few CNVs except for a prominent amplification of mouse distal chromosome 11. We identified several candidate genes within this locus that could potentially cooperate with Myc and enhancetumorigenesis. Functional analyses determined that the epigenetic modifier JMJD6 cooperates with Myc to augment oncogenic transformation of normal mammary epithelial cells as well as to increase the aggressiveness and metastatic potential of Myc-driven tumors. Increased expression of JMJD6 resulted from the in vivo selection for the amplification of the distal region of chromosome 11 in Myc-overexpressing tumors. The chromosome 11 amplified locus is not exclusively specific for Myc-driven tumors but also has been found in mouse mammary gland tumors with overexpression of Erbb2, PyMT, or BRCA1 mutations (this study and [8, 13?6, 23]), which implicates JMJD6 as potentially augmenting tumorigenesis in other oncogenic pathways. Myc activation in normal cells is not capable of promoting neoplastic transformation because of the overwhelming induction of cell death triggered by Myc protein expression above normal physiological levels [47?1]. The mechanisms of Myc-induced apoptosis have been studied very extensively, and involve multipleAprelikova et al. Clinical Epigenetics (2016) 8:Page 11 ofpathways of Myc-dependent cell death and proliferati.
