This proposal will test the hypothesis that 3-phosph6inbsitide-dependent protein kinase-1 (PDK1) activates and interacts with the ff-eaten in/TCF-target gene, peroxisome proliferator-activated receptor-delta (PPARtf). to promote mammary tumorigenesis. This will be studied by the following Specific Aims:
Aim #1 : Determine the mechanism by which PDK1 increases proliferation. We will determine the role of jff-catenin/TCF-modulationdownstream of PDK1 in proliferation, invasion and stem cell self-renewal. We have reported that PDK1 and its downstream effector, PKCa, ncreased expression of the /?-cateninfi~CF target genes, cyclin D1 and c-Myc during transformation. We have now discovered that stable expression of PDK1 in ER (+) MCF-7 breast cancer cells confers estrogen-independent growth and increases ?-catenin/TCF and PPAR5-dependent transcriptional activity. Thus, the dependency of MCF-7/PDK1 cells on PPAR<5 will be examined in vitro and in nude mice in the presence and absence of treatment with a PPARJ agonist. MEC and MCF-7 cell lines stably expressing either PPARJ or PDK1 or both genes will be used to study the synergy between these genes on growth, transformation and invasion in vitro, as well as on tumorigenicity in vivo. MDA-MB-231 breast cancer cells, which express PDK1 and PPARrf, will be engineered to express dnTCF, dnPKCo, dnPDKI and dnPPAR?J under a ponasterone A-inducible promoter, to determine the dependency of growth and invasion on these signaling pathways in the presence and absence of a PPARJ agonist. MCF-7/PDK1 and MEC/PDK1 cells, as well as a newly established mammary carcinoma cell line (MC cells) exhibiting high stem cell antigen-1 (Sca-1) expression will be used to examine the role of, PDK1 signaling in stem cell self-renewal.
Aim #2 : Determine the mechanism by which PDK1 interacts with PPAR Aim #3 : Determine the genetic consequences and tumorigenic effects of PDK1 and PPARrf expression in the mammary gland. PDK1 and PPAR

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111482-05
Application #
7758332
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2006-04-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$266,540
Indirect Cost
Name
Georgetown University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Yuan, Hongyan; Lu, Jin; Xiao, Junfeng et al. (2013) PPAR? induces estrogen receptor-positive mammary neoplasia through an inflammatory and metabolic phenotype linked to mTOR activation. Cancer Res 73:4349-61
Pollock, Claire B; Yin, Yuzhi; Yuan, Hongyan et al. (2011) PPAR? activation acts cooperatively with 3-phosphoinositide-dependent protein kinase-1 to enhance mammary tumorigenesis. PLoS One 6:e16215
Upadhyay, Geeta; Yin, Yuzhi; Yuan, Hongyan et al. (2011) Stem cell antigen-1 enhances tumorigenicity by disruption of growth differentiation factor-10 (GDF10)-dependent TGF-beta signaling. Proc Natl Acad Sci U S A 108:7820-5
Pollock, Claire B; Rodriguez, Olga; Martin, Philip L et al. (2010) Induction of metastatic gastric cancer by peroxisome proliferator-activated receptor? activation. PPAR Res 2010:571783
Rodriguez, Olga C; Lai, Edwin W; Vissapragada, Sarada et al. (2009) A reduction in Pten tumor suppressor activity promotes ErbB-2-induced mouse prostate adenocarcinoma formation through the activation of signaling cascades downstream of PDK1. Am J Pathol 174:2051-60
Yin, Yuzhi; Yuan, Hongyan; Zeng, Xiao et al. (2009) Inhibition of peroxisome proliferator-activated receptor gamma increases estrogen receptor-dependent tumor specification. Cancer Res 69:687-94
Lindsay, Jaime; Jiao, Xuanmao; Sakamaki, Toshiyuki et al. (2008) ErbB2 induces Notch1 activity and function in breast cancer cells. Clin Transl Sci 1:107-15