Dr Riegel's research interests are in the role of steroid receptors and their crosstalk with growth factor signaling in human cancer. In particular, in the past four years Dr Riegel's group has focused on the role of the steroid receptor coactivator AIB1 in breast and pancreatic cancer. The major questions being addressed are related to why high levels of this amplified protein potentiate both steroid and growth factor signaling and lead to neoplasia. We are using molecular biology and biochemistry techinques to decipher these pathways.

We are also interested in developing transgenic mouse models of AIB1 in tumorigenesis . We are attempting rationale drug design to target the interfaces of AIB1 with other cellular activator proteins as potential targets in breast and pancreatic cancer. A number of papers on this research have been published from this lab in the past four years.

Selected Publications:

• Stylianou DC, Auf der Maur A, Kodack DP, Henke RT, Hohn S, Toretsky JA, Riegel AT, Wellstein A.: Effect of single-chain antibody targeting of the ligand-binding domain in the anaplastic lymphoma kinase receptor. Oncogene. July, 2009

• Lahusen T, Henke RT, Kagan BL, Wellstein A, Riegel AT.: The role and regulation of the nuclear receptor co-activator AIB1 in breast cancer. Breast Cancer Res Treat. 116:225-37, 2009

• Oh AS, Lahusen JT, Chien CD, Fereshteh MP, Zhang X, Dakshanamurthy S, Xu J, Kagan BL, Wellstein A, Riegel AT.: Tyrosine phosphorylation of the nuclear receptor coactivator AIB1/SRC-3 is enhanced by Abl kinase and is required for its activity in cancer cells. Mol Cell Biol. 28:6580-93, 2008

• Zhang W, Chen Y, Swift MR, Tassi E, Stylianou DC, Gibby KA, Riegel AT, Wellstein A.: Effect of FGF-binding protein 3 on vascular permeability. J Biol Chem. 283:28329-37, 2008

• Fereshteh MP, Tilli MT, Kim SE, Xu J, O'Malley BW, Wellstein A, Furth PA, Riegel AT.: The nuclear receptor coactivator amplified in breast cancer-1 is required for Neu (ErbB2/HER2) activation, signaling, and mammary tumorigenesis in mice. Cancer Res. 68:3697-706, 2008

• Lahusen T, Fereshteh M, Oh A, Wellstein A, Riegel AT.: Epidermal growth factor receptor tyrosine phosphorylation and signaling controlled by a nuclear receptor coactivator, amplified in breast cancer 1. Cancer Res. 67:7256-65, 2007

• Ma Y, Hu C, Riegel AT, Fan S, Rosen EM.: Growth factor signaling pathways modulate BRCA1 repression of estrogen receptor-alpha activity. Mol Endocrinol. 21:1905-23, 2007

• Mani A, Oh AS, Bowden ET, Lahusen T, Lorick KL, Weissman AM, Schlegel R, Wellstein A, Riegel AT.: E6AP mediates regulated proteasomal degradation of the nuclear receptor coactivator amplified in breast cancer 1 in immortalized cells. Cancer Res. 66:8680-6, 2006

• Kuo AH, Stoica GE, Riegel AT, Wellstein A.: Recruitment of insulin receptor substrate-1 and activation of NF-kappaB essential for midkine growth signaling through anaplastic lymphoma kinase. Oncogene. 26:859-69, 2007

• Briones VR, Chen S, Riegel AT, Lechleider RJ.: Mechanism of fibroblast growth factor-binding protein 1 repression by TGF-beta. Biochem Biophys Res Commun. 345:595-601, 2006

• Xie B, Tassi E, Swift MR, McDonnell K, Bowden ET, Wang S, Ueda Y, Tomita Y, Riegel AT, Wellstein A.: Identification of the fibroblast growth factor (FGF)-interacting domain in a secreted FGF-binding protein by phage display. J Biol Chem. 281:1137-44, 2006

• McDonnell K, Bowden ET, Cabal-Manzano R, Hoxter B, Riegel AT, Wellstein A.: Vascular leakage in chick embryos after expression of a secreted binding protein for fibroblast growth factors. Lab Invest. 85:747-55, 2005

• Tilli MT, Reiter R, Oh AS, Henke RT, McDonnell K, Gallicano GI, Furth PA, Riegel AT.: Overexpression of an N-terminally truncated isoform of the nuclear receptor coactivator amplified in breast cancer 1 leads to altered proliferation of mammary epithelial cells in transgenic mice. Mol Endocrinol. 19:644-56, 2005

• Oh A, List HJ, Reiter R, Mani A, Zhang Y, Gehan E, Wellstein A, Riegel AT.: The nuclear receptor coactivator AIB1 mediates insulin-like growth factor I-induced phenotypic changes in human breast cancer cells. Cancer Res. 64:8299-308, 2004

• Malerczyk C, Schulte AM, Czubayko F, Bellon L, Macejak D, Riegel AT, Wellstein A.: Ribozyme targeting of the growth factor pleiotrophin in established tumors: a gene therapy approach. Gene Ther. 12:339-46, 2005

• Henke RT, Haddad BR, Kim SE, Rone JD, Mani A, Jessup JM, Wellstein A, Maitra A, Riegel AT.: Overexpression of the nuclear receptor coactivator AIB1 (SRC-3) during progression of pancreatic adenocarcinoma. Clin Cancer Res. 10:6134-42, 2004

• Bowden ET, Riegel AT.: Tetracycline-regulated expression of hammerhead ribozymes in vivo. Methods Mol Biol. 252:179-94, 2004

• Reiter R, Oh AS, Wellstein A, Riegel AT.: Impact of the nuclear receptor coactivator AIB1 isoform AIB1-Delta3 on estrogenic ligands with different intrinsic activity. Oncogene. 23:403-9, 2004

• Ray R, Cabal-Manzano R, Moser AR, Waldman T, Zipper LM, Aigner A, Byers SW, Riegel AT, Wellstein A.: Up-regulation of fibroblast growth factor-binding protein, by beta-catenin during colon carcinogenesis. Cancer Res. 63:8085-9, 2003

• Kagan BL, Henke RT, Cabal-Manzano R, Stoica GE, Nguyen Q, Wellstein A, Riegel AT.: Complex regulation of the fibroblast growth factor-binding protein in MDA- MB-468 breast cancer cells by CCAAT/enhancer-binding protein beta. Cancer Res. 63:1696-705, 2003

• Lauritsen KJ, List HJ, Reiter R, Wellstein A, Riegel AT.: A role for TGF-beta in estrogen and retinoid mediated regulation of the nuclear receptor coactivator AIB1 in MCF-7 breast cancer cells. Oncogene. 21:7147-55, 2002

• Stoica GE, Kuo A, Powers C, Bowden ET, Sale EB, Riegel AT, Wellstein A.: Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. J Biol Chem. 277:35990-8, 2002

• List HJ, Reiter R, Singh B, Wellstein A, Riegel AT.: Expression of the nuclear coactivator AIB1 in normal and malignant breast tissue. Breast Cancer Res Treat. 68:21-8, 2001

• Reiter R, Wellstein A, Riegel AT.: An isoform of the coactivator AIB1 that increases hormone and growth factor sensitivity is overexpressed in breast cancer. J Biol Chem. 276:39736-41, 2001

• List HJ, Lauritsen KJ, Reiter R, Powers C, Wellstein A, Riegel AT.: Ribozyme targeting demonstrates that the nuclear receptor coactivator AIB1 is a rate-limiting factor for estrogen-dependent growth of human MCF-7 breast cancer cells. J Biol Chem. 276:23763-8, 2001

• Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, Caughey DJ, Wen D, Karavanov A, Riegel AT, Wellstein A.: Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. J Biol Chem. 276:16772-9, 2001

• Harris VK, Coticchia CM, Kagan BL, Ahmad S, Wellstein A, Riegel AT.: Induction of the angiogenic modulator fibroblast growth factor-binding protein by epidermal growth factor is mediated through both MEK/ERK and p38 signal transduction pathways. J Biol Chem. 275:10802-11, 2000

• Harris VK, Coticchia CM, List HJ, Wellstein A, Riegel AT.: Mitogen-induced expression of the fibroblast growth factor-binding protein is transcriptionally repressed through a non-canonical E-box element J Biol Chem. 275:39801, 2000

• Boyle BJ, Harris VK, Liaudet-Coopman ED, Riegel AT, Wellstein A.: Differential regulation of a fibroblast growth factor-binding protein by receptor-selective analogs of retinoic acid. Biochem Pharmacol. 60:1677-84, 2000