DF/HCC Program Affiliation

Breast Cancer
Angiogenesis, Invasion and Metastasis, Leader

DF/HCC Associations

Member, Web Advisory
Member, Center Scientific Council

Research Abstract

The frizzled are a family of seven membrane spanning proteins that act as receptors for the Wnts. The Wnts are a family of seareted glycoproteins that have a wide range of roles from axis polarity in Xenopus to tissue differentiation. By differential display, we have identified and cloned a gene that encodes for a protein (which we call FrzA) that is homologous to the extra cellular domain of the frizzled receptor. Functional studies in Xenopus, as well as biochemical analysis in vitro, indicate that FrzA can associate with Wnts and antagonize their actions. FrzA is highly expressed in differentiated, non-proliferating vascular endothelium and a variety of epithelium. We, therefore, examined FrzA expression by in situ hybridization in normal human breast tissue and in mammary tumor tissues. Normal human mammary epithelium and myoepithelium express high levels of FrzA mRNA. FrzA expression is lost in mammary epithelium of ductal carcinoma in situ (DCIS) but remains elevated in the
myopethelium. Invasive mammary carcinoma has no FrzA mRNA expression. Similarly, vascular endothelium of non-proliferating vessels express high levels of FrzA mRNA whereas endothelial cells proliferating in culture have greatly reduced or no FrzA mRNA expression. Wnt-1 has been reported to play a role in mammary tumorigenesis. In fact, the first Wnt family members were originally identified as the protooncogene site of insertion of the mouse mammary tumor virus and was called Int-1. Taken together, the implied role of Wnts in mammary tumorigenesis and the expression pattern of FrzA in breast tumors points to a possible role for FrzA in regulation mammary epithelial cell proliferation and differentiation. We are using
tissue culture models of mammary epithelial differentiation to test this hypothesis.

Publications

• Walshe TE, D'Amore PA.The Role of Hypoxia in Vascular Injury and Repair.Annu Rev Pathol 2007 Oct 17.
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• D'Amore PA.Vascular Endothelial Cell Growth Factor-A. Not Just for Endothelial Cells Anymore.Am J Pathol 2007 May 18.
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• Ramsauer M, D'Amore PA.Contextual role for angiopoietins and TGFbeta1 in blood vessel stabilization.J Cell Sci 2007 May 15;120(Pt 10):1810-7.
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• Goodwin AM, Kitajewski J, D'Amore PA.Wnt1 and Wnt5a affect endothelial proliferation and capillary length; Wnt2 does not.Growth Factors 2007 Feb;25(1):25-32.
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• Maruyama K, Asai J, Ii M, Thorne T, Losordo DW, D'Amore PA.Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing.Am J Pathol 2007 Apr;170(4):1178-91.
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• Goodwin AM, Sullivan KM, D'Amore PA.Cultured endothelial cells display endogenous activation of the canonical Wnt signaling pathway and express multiple ligands, receptors, and secreted modulators of Wnt signaling.Dev Dyn 2006 Nov;235(11):3110-20.
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• Banerjee S, Sengupta K, Dhar K, Mehta S, D'Amore PA, Dhar G, Banerjee SK.Breast cancer cells secreted platelet-derived growth factor-induced motility of vascular smooth muscle cells is mediated through neuropilin-1.Mol Carcinog 2006 Jul 17.
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• Saint-Geniez M, Maldonado AE, D'Amore PA.VEGF expression and receptor activation in the choroid during development and in the adult.Invest Ophthalmol Vis Sci 2006 Jul;47(7):3135-42.
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• Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA.Soluble endoglin contributes to the pathogene
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• Maharaj AS, Saint-Geniez M, Maldonado AE, D'Amore PA.Vascular endothelial growth factor localization in the adult.Am J Pathol 2006 Feb;168(2):639-48.
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• Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, Tomita M, Van Rooijen N, Takenaka H, D'Amore PA, Stein-Streilein J, Losordo DW, Streilein JW.Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages.J Clin Invest 2005
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• Detwiller KY, Fernando NT, Segal NH, Ryeom SW, D'Amore PA, Yoon SS.Analysis of hypoxia-related gene expression in sarcomas and effect of hypoxia on RNA interference of vascular endothelial cell growth factor A.Cancer Res 2005 Jul 1;65(13):5881-9.
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