We have been investigating the relationship between the molecular pathways that underlie embryogenesis and those that are deregulated in carcinogenesis using the mammalian prostate as a model system. Our studies of the Nkx3.1 homeobox have elucidated its functions for development and carcinogenesis of the prostate. We have found that Nkx3.1 mutant mice display defects in prostatic epithelial differentiation and are predisposed to prostate cancer initiation. Moreover, loss-of-function of Nkx3.1 collaborates with that of the Pten and p27 Kip_ tumor suppressor genes in prostate carcinoma in compound mutant mice (i.e., Nkx3.1+/-; Pten+/-; p27+/-). Finally, epigenetic loss of Nkx3.1 protein (but not its mRNA) is a hallmark of prostate carcinogenesis, and loss of its expression is accompanied by upregulation of androgen receptor. Thus, we have hypothesized that Nkx3.1 represents a key regulator of prostatic epithelial differentiation as well as a modulator of androgen signaling. We further hypothesize that cancer susceptibility due to Nkx3.1 loss-of-function is a consequence of defects in prostatic epithelial differentiation and androgen signaling. We will now investigate:
(Aim 1) The functions of Nkx3.1 in specification of prostatic epithelial differentiation using a tissue recombination approach, which provides a model system for studying epithelial and mesenchymal tissue requirements for prostatic growth and carcinogenesis.
(Aim 2) The relationship of Nkx3.1 and androgen receptor for prostate differentiation and carcinogenesis by investigating: (i) the coordinate expression of Nkx3.1 and androgen receptor in the prostate; (ii) the role of the androgen receptor as a downstream mediator of Nkx3.1 function in prostate differentiation and carcinogenesis; and (iii) the consequences of altered androgen signaling for prostate carcinogenesis in mutant mouse models.
(Aim 3) : The mechanisms underlying the cooperativity and tissue-specificity of loss-of- function of Nkx3.1, Pten, and p27 kip1 prostate carcinogenesis, by studying the contributions of candidate effectors as well as pursuing exploratory approaches to identify novel mediators of Nkx3. I, Pten, and p27 kip1 cooperativity.
(Aim 4) The regulation of Nkx3.1 protein expression in prostate development and cancer, by defining the regulatory sequences controlling Nkx3.1 protein expression, with the ultimate goal of developing a mouse model that lacks this mode of regulating Nkx3.1 protein expression. These mice will provide a valuable model for exploring the reversibility of prostate carcinogenesis in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA076501-11
Application #
7565054
Study Section
Special Emphasis Panel (ZRG1-CDF-2 (02))
Program Officer
Jhappan, Chamelli
Project Start
1998-09-01
Project End
2010-04-30
Budget Start
2008-03-27
Budget End
2010-04-30
Support Year
11
Fiscal Year
2007
Total Cost
$231,840
Indirect Cost
Name
Columbia University (N.Y.)
Department
Urology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Dutta, Aditya; Le Magnen, Clémentine; Mitrofanova, Antonina et al. (2016) Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation. Science 352:1576-80
Le Magnen, Clémentine; Dutta, Aditya; Abate-Shen, Cory (2016) Optimizing mouse models for precision cancer prevention. Nat Rev Cancer 16:187-96
Aytes, Alvaro; Mitrofanova, Antonina; Lefebvre, Celine et al. (2014) Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. Cancer Cell 25:638-651
Floc'h, Nicolas; Kinkade, Carolyn Waugh; Kobayashi, Takashi et al. (2012) Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. Cancer Res 72:4483-93
Jeong, Joseph H; Wang, Zhenxiong; Guimaraes, Alexander S et al. (2008) BRAF activation initiates but does not maintain invasive prostate adenocarcinoma. PLoS One 3:e3949
Wang, Xi; Desai, Nishita; Hu, Ya-Ping et al. (2008) Mouse Fem1b interacts with the Nkx3.1 homeoprotein and is required for proper male secondary sexual development. Dev Dyn 237:2963-72
Banach-Petrosky, Whitney; Jessen, Walter J; Ouyang, Xuesong et al. (2007) Prolonged exposure to reduced levels of androgen accelerates prostate cancer progression in Nkx3.1;Pten mutant mice. Cancer Res 67:9089-96
Gao, Hui; Ouyang, Xuesong; Banach-Petrosky, Whitney A et al. (2006) Combinatorial activities of Akt and B-Raf/Erk signaling in a mouse model of androgen-independent prostate cancer. Proc Natl Acad Sci U S A 103:14477-82
Banach-Petrosky, Whitney; Ouyang, Xuesong; Gao, Hui et al. (2006) Vitamin D inhibits the formation of prostatic intraepithelial neoplasia in Nkx3.1;Pten mutant mice. Clin Cancer Res 12:5895-901
Gao, Hui; Ouyang, Xuesong; Banach-Petrosky, Whitney A et al. (2006) Emergence of androgen independence at early stages of prostate cancer progression in Nkx3.1; Pten mice. Cancer Res 66:7929-33

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