70% of newly diagnosed invasive breast cancers express estrogen receptor-a (ER);advanced ER+ breast cancer remains an incurable disease. We will create a Center for Cancer Systems Biology (CCSB) and build predictive computational and mathematical models of how ER regulates molecular signaling and cellular functions to affect the risk of neoplastic transformation in the normal breast, and responsiveness to endocrine therapies in breast cancer. Robust predictive models will enable a greater understanding of ER action in the regulation of cell fate, leading to discoveries that contribute to reducing breast cancer mortality. A fully integrated and productive group of senior investigators with an established track-record of collaborative peer reviewed funding and publications, and joint education and training activities, will be supported by Core A: Administration, Evaluation and Planning. The critical informatics infrastructure required will be provided by Core B: Bioinformatics Infrastructure and Data Integration. Data will be obtained in a unique series of human breast cancer cells, rodent models, and human breast cancer specimens from women treated with TAM as their only form of adjuvant therapy for invasive breast cancer (Component 1). We will integrate methods from two different fields to model ER-regulated signaling (Component 2) by extracting small, subnetwork topologies by computational bioinformatics and using these models to inform mathematical modeling. Predictions from these models will be validated in vitro and in vivo, with extensive iterative modeling guided by experimental data and the robustness of model predictions.

Public Health Relevance

Over 40,000 American women will die of breast cancer this year, one every 13 minutes. We will create a new Center for Cancer Systems Biology and build predictive computational and mathematical models of how ER acts to affect breast cancer risk and responsiveness to endocrine therapies in breast cancer. A greater understanding of ER action will lead to discoveries that contribute to reducing breast cancer mortality.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA149147-05
Application #
8627139
Study Section
Special Emphasis Panel (ZCA1-SRLB-C (J1))
Program Officer
Gallahan, Daniel L
Project Start
2010-04-29
Project End
2015-02-28
Budget Start
2014-05-20
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$1,289,047
Indirect Cost
$321,205
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Wärri, Anni; Cook, Katherine L; Hu, Rong et al. (2018) Autophagy and unfolded protein response (UPR) regulate mammary gland involution by restraining apoptosis-driven irreversible changes. Cell Death Discov 4:40
Shi, Xu; Wang, Xiao; Wang, Tian-Li et al. (2018) SparseIso: a novel Bayesian approach to identify alternatively spliced isoforms from RNA-seq data. Bioinformatics 34:56-63
Stires, Hillary; Heckler, Mary M; Fu, Xiaoyong et al. (2018) Integrated molecular analysis of Tamoxifen-resistant invasive lobular breast cancer cells identifies MAPK and GRM/mGluR signaling as therapeutic vulnerabilities. Mol Cell Endocrinol 471:105-117
Beck, Tim N; Smith, Chad H; Flieder, Douglas B et al. (2017) Head and neck squamous cell carcinoma: Ambiguous human papillomavirus status, elevated p16, and deleted retinoblastoma 1. Head Neck 39:E34-E39
Chen, Xi; Shi, Xu; Hilakivi-Clarke, Leena et al. (2017) PSSV: a novel pattern-based probabilistic approach for somatic structural variation identification. Bioinformatics 33:177-183
Varghese, Rency S; Zuo, Yiming; Zhao, Yi et al. (2017) Protein network construction using reverse phase protein array data. Methods 124:89-99
Zhang, Xiyuan; Cook, Katherine L; Warri, Anni et al. (2017) Lifetime Genistein Intake Increases the Response of Mammary Tumors to Tamoxifen in Rats. Clin Cancer Res 23:814-824
Zhang, Yong-Wei; Nasto, Rochelle E; Jablonski, Sandra A et al. (2017) RNA Interference Screening to Identify Proliferation Determinants in Breast Cancer Cells. Bio Protoc 7:
Sumis, Allison; Cook, Katherine L; Andrade, Fabia O et al. (2016) Social isolation induces autophagy in the mouse mammary gland: link to increased mammary cancer risk. Endocr Relat Cancer 23:839-56
Beck, Tim N; Georgopoulos, Rachel; Shagisultanova, Elena I et al. (2016) EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer. Mol Cancer Ther 15:2486-2497

Showing the most recent 10 out of 107 publications