The long-range goals of this proposal are to identify and characterize the pathways that are used by pleiotrophin (PTN) and midkine (MK) to promote tumor growth and tumor angiogenesis in human breast cancer models. The investigator has dissected the PTN molecule physically and functionally into two independent domains that signal transformation (PTN amino acids 1-64) and angiogenesis (PTN amino acids 69-136), respectively. Both PTN 1-64 and PTN 69-136 signal tumor promotion to establish more aggressive tumor growth of already transformed cell, but only PTN 1-64 is capable of transforming untransformed cells, establishing that PTN 1-64 and PTN 69-136 signal through different pathways and cooperate with different activated oncogenic pathways. Pleiotrophin is expressed in many human breast cancers and cell lines from breast cancers but not in normal breast epithelium. Constitutive expression of PTN only """"""""partially"""""""" transforms """"""""normal"""""""" breast epithelial (MM3MG) cells, indicating that constitutive PTN signaling alone cannot transform normal breast epithelia[ cells. Furthermore, disruption of PTN signaling in human breast carcinoma MDA-MB-231 cells which constitutively express the endogenous Ptn gene reverses their aggressive growth phenotype in nude mice and PTN 1-64 and PTN 69-136 both promote aggressive growth of the weakly transformed human breast cancer MCF-7 cells. These results indicate that MCF 7 cells have activated oncogenic pathways compatible with both the angiogenic and transforming domain of PTN and that introduction of constitutive stable expression of both PTN 1-64 and PTN 69-136 provides an incremental """"""""switch"""""""" to promote aggressive growth phenotype. MK is the other only member of the PTN growth/ differentiation family. It is also highly expressed in primary breast cancers and cell lines derived from human breast cancers. Remarkably, a naturally occurring truncated mutant MK 1-3, 59-121, a structural counterpart of the PTN angiogenesis domain (PTN 69-136), is detected in 30 % of aggressive human breast cancers tissues but not in normal breast tissues. Both MK and MK1-3, 59-121 promote more aggressive tumor growth and perhaps tumor angiogenesis (in progress) when they are constitutively expressed in MCF-7 cells and inoculated into the nude mouse. To pursue these results and the long-term goals, our Specific Aims are: I. to determine if gain of function of MMTV-PTN 1-64, MMTV-PTN 69-136, MMTV-MK 1-3,5g. 121 cooperate with activated oncogenic pathways in transgenic mice and develop and/or promote tumor II. to identify, clone, and characterize the signaling molecules through which PTN signals transformation and/or tumor promotion in human breast cancer cells. The results of the proposed experiments may be very significant. They will directly test the hypothesis that PTN and MK are naturally occurring promoters of aggressive growth in mammary cancer in transgenic mouse models. They may also identify downstream molecules signaled in tumor promotion and potential therapeutic products in human breast cancer in man.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Hematology Subcommittee 2 (HEM)
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Scripps Research Institute
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Perez-Pinera, P; Alcantara, S; Dimitrov, T et al. (2006) Pleiotrophin disrupts calcium-dependent homophilic cell-cell adhesion and initiates an epithelial-mesenchymal transition. Proc Natl Acad Sci U S A 103:17795-800
Zhang, Nan; Zhong, Rong; Perez-Pinera, Pablo et al. (2006) Identification of the angiogenesis signaling domain in pleiotrophin defines a mechanism of the angiogenic switch. Biochem Biophys Res Commun 343:653-8
Ezquerra, Laura; Herradon, Gonzalo; Nguyen, Trang et al. (2006) Midkine is a potent regulator of the catecholamine biosynthesis pathway in mouse aorta. Life Sci 79:1049-55
Christman, Karen L; Fang, Qizhi; Kim, Anne J et al. (2005) Pleiotrophin induces formation of functional neovasculature in vivo. Biochem Biophys Res Commun 332:1146-52
Ezquerra, Laura; Herradon, Gonzalo; Nguyen, Trang et al. (2005) Midkine, a newly discovered regulator of the renin-angiotensin pathway in mouse aorta: significance of the pleiotrophin/midkine developmental gene family in angiotensin II signaling. Biochem Biophys Res Commun 333:636-43
Herradon, Gonzalo; Ezquerra, Laura; Nguyen, Trang et al. (2005) Midkine regulates pleiotrophin organ-specific gene expression: evidence for transcriptional regulation and functional redundancy within the pleiotrophin/midkine developmental gene family. Biochem Biophys Res Commun 333:714-21
Pariser, Harold; Ezquerra, Laura; Herradon, Gonzalo et al. (2005) Fyn is a downstream target of the pleiotrophin/receptor protein tyrosine phosphatase beta/zeta-signaling pathway: regulation of tyrosine phosphorylation of Fyn by pleiotrophin. Biochem Biophys Res Commun 332:664-9
Pariser, Harold; Perez-Pinera, Pablo; Ezquerra, Laura et al. (2005) Pleiotrophin stimulates tyrosine phosphorylation of beta-adducin through inactivation of the transmembrane receptor protein tyrosine phosphatase beta/zeta. Biochem Biophys Res Commun 335:232-9
Wang, Zhaoyi; Zhang, Xintian; Shen, Peng et al. (2005) Identification, cloning, and expression of human estrogen receptor-alpha36, a novel variant of human estrogen receptor-alpha66. Biochem Biophys Res Commun 336:1023-7
Pariser, Harold; Herradon, Gonzalo; Ezquerra, Laura et al. (2005) Pleiotrophin regulates serine phosphorylation and the cellular distribution of beta-adducin through activation of protein kinase C. Proc Natl Acad Sci U S A 102:12407-12

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