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

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Sathyamoorthy, Neeraja
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Georgetown University
Schools of Medicine
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Yuan, Hongyan; Lu, Jin; Xiao, Junfeng et al. (2013) PPARδ 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) PPARδ 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 receptorδ 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
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