Prostate cancer is a prevalent disease among men in the United Sates. Current therapies are limited, and there is no successful treatment once tumor cells have spread to other tissues. Discovery of successful therapies is still a truly important challenge. However, identification of new targets for cancer therapy requires a thorough understanding of the molecular processes that lead to cell transformation. Recent studies have shown that transcription factor Egr-1 (Early Growth Response-l) is present at much higher levels in human prostate tumors as opposed to normal cells. An important result from J. Milbrandt's laboratory was that lack of Egr-1 expression significantly delayed the progression of prostate carcinoma in mouse models. However, there has been no study to directly assess the role of Egr-1 in tumor initiation or to measure the effect of specifically blocking Egr-1 expression in prostate cancer cells. These issues are critical and need to be tested before designing Egr-based therapies. Our approach is based on the rationale that blocking Egr-1 expression in prostate cancer cells will inhibit cell proliferation and eventually stop tumor growth. We describe the design and obtaining of specific antisense oligonucleotides that block Egr-1 function. Preliminary results show that inhibition of Egr-1 expression in prostate cancer cell lines actually hampered cell proliferation and inhibited the capacity of these cells to form colonies in culture dishes and in soft agar, two hallmarks of transformed cells. Conversely, we observed that ectopic expression of Egr-1 in 267B prostate cells induced transformation. These data point to Egr-1 as a potential participant in prostate cancer progression and therefore, as a potential molecular target for prostate cancer therapy. The objectives of the present proposal are to: validate Egr-1 as a target for prostate cancer therapy in human systems and test the efficacy of the antisense oligonucleotide in animal models for prostate cancer (Specific Aim 1); identify Egr-1 functions in prostate cells and investigate the molecular mechanisms that contribute to Egr-1 oncogenic properties (Specific Aim 2). Demonstration that Egr-1 acts as an oncogene in prostate cancer challenges an existing paradigm given that this transcription factor is most often believed to have tumor suppressor effects in other cell types. The proposed study should lead to a novel understanding of the molecular mechanisms underlying prostate cancer progression, validate a target for prostate cancer treatment and design a novel therapeutic approach.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102688-04
Application #
7204207
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Arya, Suresh
Project Start
2004-04-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$289,700
Indirect Cost
Name
Sidney Kimmel Cancer Center
Department
Type
DUNS #
789644697
City
San Diego
State
CA
Country
United States
Zip Code
92121
Abedinpour, Parisa; Baron, Veronique T; Welsh, John et al. (2011) Regression of prostate tumors upon combination of hormone ablation therapy and celecoxib in vivo. Prostate 71:813-23
Sauer, L; Gitenay, D; Vo, C et al. (2010) Mutant p53 initiates a feedback loop that involves Egr-1/EGF receptor/ERK in prostate cancer cells. Oncogene 29:2628-37
Gitenay, Delphine; Baron, VĂ©ronique T (2009) Is EGR1 a potential target for prostate cancer therapy? Future Oncol 5:993-1003
Gaggioli, Cedric; Robert, Guillaume; Bertolotto, Corine et al. (2007) Tumor-derived fibronectin is involved in melanoma cell invasion and regulated by V600E B-Raf signaling pathway. J Invest Dermatol 127:400-10
Yu, J; Baron, V; Mercola, D et al. (2007) A network of p73, p53 and Egr1 is required for efficient apoptosis in tumor cells. Cell Death Differ 14:436-46
Baron, V; Adamson, E D; Calogero, A et al. (2006) The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFbeta1, PTEN, p53, and fibronectin. Cancer Gene Ther 13:115-24