This Program Project application will Investigate the molecular mechanisms of prostate cancer initiation. The proposed studies will be pursued by a highly-integrated Interdisciplinary team of investigators who have substantial track records in prostate cancer research, as well as in collaborative interactions with each other. Our proposal has a central focus on the role of NKX3.1, a key regulator of gene expression programs in the prostate epithelium whose expression is down-regulated during prostate cancer initiation. Recent studies by members of our research team have shown that Nkx3.1 is a marker for a prostate epithelial stem cell population that is a cell type of origin for prostate cancer in mice, and that Nkx3.1 plays a role in stem cell maintenance. Furthermore, NKX3.1 participates in the earliest molecular events involved in the response to DNA damage, while NKX3.1 loss predisposes to increased oxidative damage, decreased survival after DNA damage, and cellular senescence. Thus, analysis of NKX3.1 function in prostate tumorigenesis represents an excellent model for investigating cancer initiation. We will pursue three interrelated projects that will investigate the molecular mechanisms of prostate cancer initiation using genetically-engineered mouse and cell culture models, together with essential validation using human xenografts and clinical specimens. Project 1 (Shen) will investigate the potential cell type(s) of origin for prostate cancer in mouse models, and will determine whether these cells of origin can give rise to tumor-initiating cells. Project 2 (Abate-Shen) will analyze the roles for Nkx3.1 in prostate epithelial specification and cellular senescence, and will identify Nkx3.1 target genes through genome-wide analyses coupled with functional validation in mouse and human prostate. Project 3 (Gelmann) will investigate the role of Nkx3.1 in the DNA damage response in cell culture and mouse models. These Projects will be assisted by Core A (Cordon-Cardo), which will provide pathology support for the Projects and will examine the incidence and co-localization of known molecular events in prostate cancer initiation, as well as by Core B (Shen), which will provide administrative, bioinformatic, and biostatistical support for the overall Program.
The earliest events that increase susceptibility of the aging male represent critical targets in the battle against prostate cancer. Thus, therapeutic intervention at these gatekeeper events should greatly impair the development and progression of clinical prostate cancer. Detailed understanding of the molecular mechanisms of cancer initiation will provide key insights into chemoprevention and therapeutic targets at the level of individual proteins and signaling pathways, as well as stem cell populations that represent the heart of malignancy.
|Le Magnen, ClÃ©mentine; Dutta, Aditya; Abate-Shen, Cory (2016) Optimizing mouse models for precision cancer prevention. Nat Rev Cancer 16:187-96|
|Dutta, Aditya; Le Magnen, ClÃ©mentine; Mitrofanova, Antonina et al. (2016) Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation. Science 352:1576-80|
|Zhang, Hailan; Zheng, Tian; Chua, Chee Wai et al. (2016) Nkx3.1 controls the DNA repair response in the mouse prostate. Prostate 76:402-8|
|Mitrofanova, Antonina; Aytes, Alvaro; Zou, Min et al. (2015) Predicting Drug Response in Human Prostate Cancer from Preclinical Analysis of In Vivo Mouse Models. Cell Rep 12:2060-71|
|Bowen, Cai; Zheng, Tian; Gelmann, Edward P (2015) NKX3.1 Suppresses TMPRSS2-ERG Gene Rearrangement and Mediates Repair of Androgen Receptor-Induced DNA Damage. Cancer Res 75:2686-98|
|Shibata, Maho; Shen, Michael M (2015) Stem cells in genetically-engineered mouse models of prostate cancer. Endocr Relat Cancer 22:T199-208|
|Shen, Michael M (2015) Cancer: The complex seeds of metastasis. Nature 520:298-9|
|Shen, Michael M (2015) Illuminating the Properties of Prostate Luminal Progenitors. Cell Stem Cell 17:644-6|
|Song, Liang-Nian; Silva, Jose; Koller, Antonius et al. (2015) The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase. Mol Cancer Res 13:913-22|
|Lee, Suk Hyung; Shen, Michael M (2015) Cell types of origin for prostate cancer. Curr Opin Cell Biol 37:35-41|
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