Our recent work has focused on understanding which mouse models of human mammary cancer represent specific sub-types of human breast cancer in order 1) to better understand what determines the mechanisms that underlie the lineage determinants of breast cancer sub-types, and 2) which models best represent particular sub-types of human breast cancer for use in pre-clinical testing for those sub-types. We previously have determined that mouse models where functions of both p53 and Rb have been compromised exhibit a very comprehensive, integrated genetic network of genes related to replication, DNA synthesis and repair, chromosome maintenance, proliferation, and apoptosis. This network is highly represented in- and predictive of basal-type breast cancer and the most aggressive forms of prostate and lung cancers. We hypothesized that many of these previously unrecognized genes related to basal type tumors may be potentially important targets for anti-cancer therapies and we are pursuing this experimentally using a custom siRNA library screen. To this end, we have identified CHK1 and RRM1 and RRM2 as being critical targets for TNBC. We have performed in vitro and in vivo studies and have demonstrated that the combination of a CHK1 inhibitor and gemcitabine work synergistically to inhibit growth of TNBC cells. Based upon these results, a clinical trial of this combination therapy is being executed. We have also expanded our work related to understanding global genomic changes that occur in GEM mammary tumor models based upon the initiating oncogenic event. We have developed gene expression, array CGH and miRNA datasets from the same tumors from eight mammary tumor models. We hypothesize that cancer may evolve differently depending upon the initiating oncogenic event and that understanding these processes may provide insights into identifying secondary changes that are critical for tumor development and progression. We have determined that models with compromised function of p53, Rb or BRCA1 evolve into a basal-type of mammary cancer, whereas the MMTV-oncogene driven models reflect some features of a luminal phenotype, perhaps in large part by not clustering with basal tumors. Interestingly, significant differences in genomic copy number changes and ploidy also distinguish these various mammary tumor models. Analysis of miRNA expression patterns also differ significantly between the models and the functional significance of this is being explored and compared to miRNA expression patterns in human breast cancer. Many of these distinguishing molecular features may be related to the lineage specificity of the mammary tumors that develop. We have recently used a novel informatics approach to correlate inverse relationships between miRNA and mRNA expression of predicted miRNA targets to identify new miRNA targets that may be related to tumor lineage and biology. Using array CGH, we have identified specific chromosomal regions where specific DNA copy number changes tend to occur based upon the initiating oncogenic event. We are pursuing these results to identify secondary changes that are required for tumorigenesis to occur and relate these changes to human cancers. We have continued to characterize several new mouse models of mammary cancer that demonstrate the critical interactions of genetic mutations in altering the histologic tumor phenotype that develops. Preliminary analyses indicate that the loss of expression of a particular genes can switch the tumor lineage from an adenosquamous to adencarcinoma phenotype. The molecular mechanisms related to this lineage specificity are being further explored through microarray analyses and functional studies. We have also begun to demonstrate that targeted expression of key transcription factors to breast cancer cells can significantly alter their phenotype and biologic properties. We are pursuing this approach using the transcription factor GATA3 as a means of novel differentiation therapy with the goal of reducing aggressive and metastatic properties of breast cancer cells. We have demonstrated that overexpression of GATA3 in TNBC cells dramatically reduces their agressive behavior, leads to mesenchymal-to-epithelial transition, and significantly reduces metastases through the reduction in expression of lysyl oxidase. Ultimately, this could have translational value for prevention or therapeutic approaches. Ongoing work using genomic technologies is determining how polycomb genes can influence the action of oncogenes leading to increased tumorgenicity and metastases. We have previously shown that co-expression of BMI1 with RAS leads to aggressive tumor formation and metastases which is not observed when these genes are singly expressed . Overall, the results from these studies will provide important new insights into molecular determinants of TNBC, potential new clinically translatable targets for therapy and mechanisms of metastases.
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