14 research outputs found
Heterogeneity of mammary lesions represent molecular differences
BACKGROUND: Human breast cancer is a heterogeneous disease, histopathologically, molecularly and phenotypically. The molecular basis of this heterogeneity is not well understood. We have used a mouse model of DCIS that consists of unique lines of mammary intraepithelial neoplasia (MIN) outgrowths, the premalignant lesion in the mouse that progress to invasive carcinoma, to understand the molecular changes that are characteristic to certain phenotypes. Each MIN-O line has distinguishable morphologies, metastatic potentials and estrogen dependencies. METHODS: We utilized oligonucleotide expression arrays and high resolution array comparative genomic hybridization (aCGH) to investigate whole genome expression patterns and whole genome aberrations in both the MIN-O and tumor from four different MIN-O lines that each have different phenotypes. From the whole genome analysis at 35 kb resolution, we found that chromosome 1, 2, 10, and 11 were frequently associated with whole chromosome gains in the MIN-Os. In particular, two MIN-O lines had the majority of the chromosome gains. Although we did not find any whole chromosome loss, we identified 3 recurring chromosome losses (2F1-2, 3E4, 17E2) and two chromosome copy number gains on chromosome 11. These interstitial deletions and duplications were verified with a custom made array designed to interrogate the specific regions at approximately 550 bp resolution. RESULTS: We demonstrated that expression and genomic changes are present in the early premalignant lesions and that these molecular profiles can be correlated to phenotype (metastasis and estrogen responsiveness). We also identified expression changes associated with genomic instability. Progression to invasive carcinoma was associated with few additional changes in gene expression and genomic organization. Therefore, in the MIN-O mice, early premalignant lesions have the major molecular and genetic changes required and these changes have important phenotypic significance. In contrast, the changes that occur in the transition to invasive carcinoma are subtle, with few consistent changes and no association with phenotype. CONCLUSION: We propose that the early lesions carry the important genetic changes that reflect the major phenotypic information, while additional genetic changes that accumulate in the invasive carcinoma are less associated with the overall phenotype
Epigenetic Silencing of CCAAT/Enhancer-binding Protein δ Activity by YY1/Polycomb Group/DNA Methyltransferase Complex*
Human CCAAT/enhancer-binding protein δ (CEBPD) has been reported as a
tumor suppressor because it both induces growth arrest involved in
differentiation and plays a crucial role as a regulator of pro-apoptotic gene
expression. In this study, CEBPD gene expression is down-regulated,
and “loss of function” alterations in CEBPD gene
expression are observed in cervical cancer and hepatocellular carcinoma.
Suppressor of zeste 12 (SUZ12), a component of the polycomb repressive complex
2 (PRC2), silences CEBPD promoter activity, enhancing the methylation
of exogenous CEBPD promoter through the proximal CpG islands.
Moreover, this molecular approach is consistent with the opposite mRNA
expression pattern between SUZ12 and CEBPD in cervical
cancer and hepatocellular carcinoma patients. We further demonstrated that
Yin-Yang-1 (YY1) physically interacts with SUZ12 and can act as a mediator to
recruit the polycomb group proteins and DNA methyltransferases to participate
in the CEBPD gene silencing process. Taking these results into
consideration, we not only demonstrate the advantage of SUZ12-silenced
CEBPD expression in tumor formation but also clarify an in
vivo evidence for YY1-mediated silencing paths of SUZ12 and DNA
methyltransferases on the CEBPD promoter