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 planned.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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC005740-20
Application #
8552587
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2012
Total Cost
$1,120,018
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Min, Dong-Joon; He, Siping; Green, Jeffrey E (2016) Birinapant (TL32711) Improves Responses to GEM/AZD7762 Combination Therapy in Triple-negative Breast Cancer Cell Lines. Anticancer Res 36:2649-57
Thompson, Matthew D; Grubbs, Clinton J; Bode, Ann M et al. (2015) Lack of effect of metformin on mammary carcinogenesis in nondiabetic rat and mouse models. Cancer Prev Res (Phila) 8:231-9
Ahn, Sung Gwe; Dong, Seung Myung; Oshima, Akira et al. (2013) LOXL2 expression is associated with invasiveness and negatively influences survival in breast cancer patients. Breast Cancer Res Treat 141:89-99
Chu, Isabel M; Lai, Wei-Chu; Aprelikova, Olga et al. (2013) Expression of GATA3 in MDA-MB-231 triple-negative breast cancer cells induces a growth inhibitory response to TGFýý. PLoS One 8:e61125
Hu, Ying; Bai, Ling; Geiger, Thomas et al. (2013) Genetic Background May Contribute to PAM50 Gene Expression Breast Cancer Subtype Assignments. PLoS One 8:e72287
Rodriguez, Virginia; Vasudevan, Sona; Noma, Akiko et al. (2012) Structure-function analysis of human TYW2 enzyme required for the biosynthesis of a highly modified Wybutosine (yW) base in phenylalanine-tRNA. PLoS One 7:e39297
Chu, I M; Michalowski, A M; Hoenerhoff, M et al. (2012) GATA3 inhibits lysyl oxidase-mediated metastases of human basal triple-negative breast cancer cells. Oncogene 31:2017-27
Hudson, Tamaro S; Carlson, Bradley A; Hoeneroff, Mark J et al. (2012) Selenoproteins reduce susceptibility to DMBA-induced mammary carcinogenesis. Carcinogenesis 33:1225-30
Bennett, Christina N; Tomlinson, Christine C; Michalowski, Aleksandra M et al. (2012) Cross-species genomic and functional analyses identify a combination therapy using a CHK1 inhibitor and a ribonucleotide reductase inhibitor to treat triple-negative breast cancer. Breast Cancer Res 14:R109
Zhu, Min; Yi, Ming; Kim, Chang Hee et al. (2011) Integrated miRNA and mRNA expression profiling of mouse mammary tumor models identifies miRNA signatures associated with mammary tumor lineage. Genome Biol 12:R77

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