Proposal: Identifying a network of miRNAs and genes that regulate breast tumor metastasis Abstract Metastasis is the major cause of death in breast cancer patients. However, the molecular mechanisms underlying tumor initiation and metastasis are not clear. We have recently identified tumor initiation cells (TICs) from human breast tumors 1,2. TICs carry certain properties of stem cells, are more resistant to conventional cancer therapies, and are involved in tumor metastasis. How to effectively target TICs or metastasis initiating cells (MICs) thus becomes one of the most propelling questions. Endogenous single strand small RNAs of 20- 22 nucleotides in length, known as microRNAs (miRNAs, miRs), have emerged to be powerful regulators of tumor progression 3-15. In this project, we aim to characterize novel miRs that regulate human breast cancer initiation and metastasis and identify their target genes. Then in our future endeavors, we will examine miR regulation mechanisms at the transcriptional level and further translate our understanding to clinical applications, such as novel cancer biomarkers or therapeutics. Most previous metastasis models are limited in their ability to fully represent human tumors, due to genetic changes accumulated in culture for human cancer cell lines, genetic differences in mouse tumor models compared to human tumors, and bypassing the natural steps of metastasis via bloodstream inoculations. This project will take advantage of our recently established human-in-mouse breast cancer models, which are derived from clinical tumor specimens and develop spontaneous lung or lymph node metastases upon orthotopic transplantation into mouse mammary fat pads. To closely monitor breast tumor initiation and metastasis in vivo, we have also transduced primary cancer cells with optical reporters and improved the detection sensitivity to 10 cells in vivo via non-invasive bioluminescence imaging. MiRs are more stable and resistant to analysis protocols than mRNAs, thus serving as promising novel cancer biomarkers. Furthermore, they are endogenous small RNAs with little toxicity compared to compound drugs; therefore hold the promise to be developed as innovative cancer therapeutics. Our long-term goal is to combine our understanding of tumor initiation and metastasis with knowledge in multi- disciplinary technology (such as chemistry and bioengineering) to improve clinical medicine and reduce cancer mortality. Transcription Factors In vivo Tumor initiation metastasis Future 1 Novel miRNAs 1 Future 2 In vitro Tumor growth Cell invasion Target Differentiation Genes Drug-resistance Preclinical Biomarkers Therapeutics 2 A schematic figure of aims: (1) to characterize and validate miRNA candidate functions, (2) to identify miRNA targets and their importance in BTICs and metastasis, (Future 1) transcriptional regulation of miRNAs by transcriptional factors, and (Future 2) preclinical studies of miRNAs and genes serving as novel biomarkers and/or therapeutic targets for breast cancer.

Public Health Relevance

Project Relevance Using patient tumor-derived human breast cancer models, this project aims to identify a novel network of microRNAs and their target genes critical for breast cancer initiation and/or metastasis. Newly identified microRNAs are promising candidates for novel biomarkers and therapeutics for cancer medicine. I am a permanent resident in the United States. I am in my 5th year of postdoctoral training at The University of Chicago, and am ready to make a timely transition to an independent investigator upon completing the one-year mentored phase. This application proposes a 1-year mentored phase (100% effort) and a 3-year independent phase (80% effort) to complete the research and training goals.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
3R00CA160638-05S1
Application #
9459151
Study Section
Special Emphasis Panel (NSS)
Program Officer
Ogunbiyi, Peter
Project Start
2014-02-01
Project End
2018-01-31
Budget Start
2017-01-01
Budget End
2018-01-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Thiagarajan, Praveena S; Sinyuk, Maksim; Turaga, Soumya M et al. (2018) Cx26 drives self-renewal in triple-negative breast cancer via interaction with NANOG and focal adhesion kinase. Nat Commun 9:578
Chen, Wenjing; Hoffmann, Andrew D; Liu, Huiping et al. (2018) Organotropism: new insights into molecular mechanisms of breast cancer metastasis. NPJ Precis Oncol 2:4
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Yu, Shuiliang; Parameswaran, Neetha; Li, Ming et al. (2017) CRABP-II enhances pancreatic cancer cell migration and invasion by stabilizing interleukin 8 expression. Oncotarget 8:52432-52444
Ramos, Erika K; Hoffmann, Andrew D; Gerson, Stanton L et al. (2017) New Opportunities and Challenges to Defeat Cancer Stem Cells. Trends Cancer 3:780-796
Samaeekia, Ravand; Adorno-Cruz, Valery; Bockhorn, Jessica et al. (2017) miR-206 Inhibits Stemness and Metastasis of Breast Cancer by Targeting MKL1/IL11 Pathway. Clin Cancer Res 23:1091-1103
Qadir, Abdul S; Ceppi, Paolo; Brockway, Sonia et al. (2017) CD95/Fas Increases Stemness in Cancer Cells by Inducing a STAT1-Dependent Type I Interferon Response. Cell Rep 18:2373-2386
Dashzeveg, Nurmaa K; Taftaf, Rokana; Ramos, Erika K et al. (2017) New Advances and Challenges of Targeting Cancer Stem Cells. Cancer Res 77:5222-5227
Kibria, Golam; Ramos, Erika K; Lee, Katelyn E et al. (2016) A rapid, automated surface protein profiling of single circulating exosomes in human blood. Sci Rep 6:36502

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