The Brekken Laboratory

Rolf Andrew Brekken, Ph.D.
Dr. Rolf Brekken is currently the Effie Marie Cain Research Scholar in Angiogenesis Research.  He received his Bachelor of Arts degree from Luther College in Decorah, Iowa in 1991 and graduated from UT Southwestern Graduate School of Biomedical Sciences in 1999.  His graduate research was focused in the use of Vascular Endothelial Growth Factor (VEGF) as a target for the therapy of solid tumors.  In August 2002, he completed his postdoctoral training under Dr. E. Helene Sage in the Department of Vascular Biology at the Hope Heart Institute in Seattle, Washington.  His research interests include angiogenesis and extracellular matrix remodeling in tumors and the development of novel tumor targeting and drug delivery agents for the therapy of pancreatic cancer.  Dr. Brekken has a secondary appointment in the Department of Pharmacology at UT Southwestern Medical Center.

The Brekken laboratory is located in the Hamon Center for Therapeutic Oncology Research and studies tumor - host interactions with a particular emphasis on extracellular matrix (ECM) and angiogenesis.

Current projects in the lab are focused on the function of matricellar proteins (e.g., SPARC, hevin and fibulin-5) as regulators of ECM remodeling and angiogenesis.  The lab also has a strong interest in testing novel antiangiogenic and vascular targeting agents in orthotopic models of cancer.


Selected recent publications

Holloway SE, Beck AW, Girard L, Raffat MR, Barnett CC, Brekken RA,  and Fleming JB.  (2005)  Increased expression of Cyr61 (CCN1) in human pancreatic cancer metastases.  J Am Coll Surg, 200, 371-377.

Fleming JB, Shen G, Holloway SE, Davis M, and Brekken RA.  (2005) Molecular consequences of silencing mutant K-ras in pancreatic cancer cells:  justification of K-ras directed therapy.  Mol Can Res, 3,413-423.

Korpanty G, Grayburn PA, Shohet RV, and Brekken RA.  (2005) Targeting vascular endothelium with avidin microbubbles.  Ultrasound Med Biol, 31(9):1279-83.

Beck AW, Luster TA, Miller AF, Holloway SE, Conner CR, Barnett CC, Thorpe PE, Fleming JB, Brekken RA.  (2006) Combination of a monoclonal antiphoshatidylserine antibody with gemcitabine strongly inhibits the growth and metastasis of orthotopic pancreatic tumors in mice.  Int J Cancer, 118(10):2639-43.

Nozaki M, Sakurai E, Raisler BJ, Baffi JZ, Witta J, Ogura Y, Brekken RA, Sage EH, Ambati BK, and Ambati J.  (2006) Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A.  J Clin Invest, 116(2):422-9.

Hohenstein B, Hausknecht B, Boehmer K, Riess R, Brekken RA, Hugo CP.  (2006) Local VEGF activity but not VEGF expression is tightly regulated during diabetic nephropathy in man.  Kidney Int,  69(9):1654-61.

Holloway SE, Beck AW, Shivakumar L, Shih J, Fleming JB, and Brekken RA.  (2006) Selective blockade of VEGF Receptor 2 with an antibody against tumor-derived VEGF controls the growth of human pancratic adenocarcinoma xenografts.  Annals of Surg Onc, 13(8):1145-55.

Santarelli JG, Yung CY, Udani V, Cheshier S, Wagers A, Brekken RA, Weissman I, an Tse V.  (2006)  Incorporation of bone marrow-derived Flk-1-expressing CD34+ cells in the endothelium of tumor vessels in mouse brain.  Neurosurgery, 59(2):374-82; discussion 374-82.

Liang Y, Brekken RA, and Hyder SM.  (2006)  Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the antiproliferative activity of anti-hormones.  Endocr Relat Cancer, 13(3):905-19.

Korpanty G, Carbon JG, Grayburn PA, Fleming JB, and Brekken RA.  Monitoring response to anti-cancer therapy by targeting microbubbles to tumor vasculature.  Clin Can Res, (in press).


The Euhus Laboratory

David M. Euhus, M.D.
Dr. David Euhus is the Marilyn R. Corrigan Distinguished Chair in Breast Cancer Surgery.  His translational research program is a bridge between the Mary L. Brown Breast Cancer Genetics and Risk Assessment Clinic and the basic science laboratories of the Hamon Center for Therapeutic Oncology Research.  Women with family histories of breast cancer or biopsy results showing high risk breast preneoplasia undergo a comprehensive evaluation that includes computerized risk modeling using  custom software similar to the popular CancerGene program which he developed.  Many women elect to participate in one of the breast epithelial cell sampling studies and undergo random fine needle aspiration biopsy and/or nipple duct lavage.   Breast epithelial cells are evaluated for cytological signs of high risk preneoplasia and the DNA from these cells is tested for promoter region methylation of tumor suppressor genes (RASSF1A, APC, RAR -b, H-Cadherin,  Cyclin D2, or TWIST) and for amplification of activating oncogenes such as Her -2/neu, Cyclin D1 and C-MYC.  The combination of extensive epidemiological breast cancer risk information and sophisticated analysis of biomarker expression in benign breast epithelium allows rapid screening of potential biomarkers in the pursuit of accurate individualized breast cancer risk assessment, and is contributing to our knowledge of the molecular changes responsible for malignant transformation of breast epithelium.

Because genomic instability appears to be a central feature of breast cancer, the laboratory is also investigating individual differences in DNA repair response after exposure to DNA damaging agents that can be found in the environment such as benzo[a]pyrene and radiation.  These studies involve short term culture and characterization of myoepithelial and luminal epithelial breast cells  as well as extensive genotyping of DNA repair enzymes. 

Funded Studies

A randomized prospective double blind trial to identify biomarkers in breast epithelium that are modulated by tamoxifen but not placebo.

Markers of growth dysregulation in breast epithelium obtained by random fine needle aspiration biopsy in women at high risk for breast cancer.

Serial Evaluation of Ductal Epithelium by Nipple Duct Lavage.


Selected Recent Publications

Euhus DM, Smith KC, Robinson L, Stukey FA, Olopade OI, Cummings S, Garber JE, Chittenden A, Mills GB, Reiger P, Esserman L, Crawford B, Hughes KS, Roche C, Ganz P, Seldon J, Fabian CJ, Klemp J, Tomlinson G.  Pretest Prediction of BRCA1 or BRCA2 Mutation by Risk Counselors and the Computer Program BRCAPRO.  J Natl Cancer Inst, 2002;94:844-51.  

Euhus DM, Cler L, Sivapurkar N, Michgrub S, Peters GN, Leitch AM, Heda S, Gazdar AF.  Loss of heterozygosity in benign breast epithelium in relation to breast cancer risk.  J Natl Cancer Inst, 2002;94:858-60. 

Sakaguchi M, Dudak MW, Virmani A, Peters GN, Leitch AM, Saboorian H, Gazdar AF, Euhus DM.  Clinical relevance of reverse transcriptase polymerase chain reaction for the detection of axillary lymph node metastases in breast cancer.  Ann Surg Oncol, 2003;10(2):117-125.

Euhus DM.   Cytokeratin staining and other sentinel node controversies.   Clin Breast Cancer, 2003 Apr;4 Suppl 1:S49-54.  

Wilkinson NW, Euhus DM.  Adenoviral-mediated gene transfer of interleukin-2 in a human breast cancer cell line and a fresh primary cancer culture.  J Invest Surg, 2003 Jul-Aug;16(4):203-8. 

Virmani A, Rathi A, Sugio K, Sathyanarayana UG, Toyooka S, Kischel FC, Tonk V, Padar A, Takahashi T, Roth JA, Euhus DM, Minna JD, Gazdar AF.  Aberrant methylation of TMS1 in small cell, non small cell lung cancer and breast cancer.  Int J Cancer, 2003 Aug 20;106 (2):198-204. 

Virmani A, Rathi A, Heda S, Sugio K, Lewis C, Tonk V, Takahashi T, Roth JA, Minna JD, Euhus DM, Gazdar AF.  Aberrant methylation of the cyclin D2 promoter in primary  small cell, nonsmall cell lung and breast cancers.  Int J Cancer, 2003 Nov 10;107(3):341-5.

Euhus DM.  Risk Modeling in Breast Cancer.  The Breast Journal, 2004 10(1):S10-S12.

Meng S, Tripathy D, Shete S, Ashfaq R, Haley B, Perkins S, Beitsch P, Khan A, Euhus D, Osborne C, Frenkel E, Hoover S, Leitch M, Clifford E, Vitetta E, Morrison L, Herlyn D, Terstappen LWMM, Fleming T, Fehm T, Tucker T, Lane N, Wang J, Uhr J.  HER-2 gene amplification can be acquired as breast cancer progresses.  Proceedings of the National Academy of Sciences of the United States of America, June 22, 2004, Vol. 101, No. 25, 9393-9398. 

Maddux AJ, Ashfaq R, Naftalis E, Leitch AM, Hoover S, Euhus D.  Patient and Duct Selection for Nipple Duct Lavage.  Am J Surg, 2004 Oct; 188(4):390-394. 

Bu D, Cler L, Lewis C, Euhus D.   A Variant of DNA Polymerase-Beta is not Cancer Specific.  Journal of Investigative Surgery, 17:327-331, 2004. 

Stadler RF, Gregorcyk SG, Euhus DM, Place RJ, Huber PJ, Simmang CL.  Outcome of HIV-infected patients with invasive squamous-cell carcinoma of the anal canal in the era of highly active antiretroviral therapy.  Dis Colon Rectum, 47(8):1305-9, 2004 Aug. 

Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D, Haley B, Morrison L, Fleming TP, Herlyn D, Terstappen LW, Fehm T, Tucker TF, Lane N, Wang J, Uhr JW.  Circulating Tumor Cells in Patients with Breast Cancer Dormancy.  Clin Cancer Res, 2004 Dec 15;10(24):8152-62. 

Lewis C, Cler L, Bu D, Zochbauer-Muller S, Milchgrub S, Naftalis E, Leitch AM, Minna J, Euhus DM.  Promoter Hypermethylation in Benign Breast Epithelium in Relation to Predicted Breast Cancer Risk.  Clin Cancer Res, 2005 Jan 1;11(1):166-172. 

Maddux AJ, Ashfaq R, Naftalis E, Leitch AM, Hoover S, Euhus DM.  Reproducibility of Cytological Atypia in Repeat Nipple Duct Lavage.  Cancer, 2005 Mar 15:103(6):1129-36. 

Patterson A, Davis H, Euhus D, Neuhausen S, Strong L, Tomlinson G.  Recruitment for Breast Cancer Predisposition Studies in an Underserved African-American Population.  Breast J, 2005 Jan-Feb;11(1):79-82. 

Coyle Y, Minhajuddin A, Euhus D, Hynan L.  An Ecological Study of the Association of Environmental Chemicals on Breast Cancer Incidence in Texas.  Breast Cancer Res Treat, 2005 Jul;92(2):107-14. 

Euhus DM.  Clinical Relevance of Circulating Tumor Cells in the Management of Breast Cancer.  Biological Therapy of Breast Cancer, February 2006. 

Chen S, Iversen ES, Friebel T, Finkelstein, Weber B, Eisen A, Peterson L, Schildkraut JM, Isaacs C, Peshkin BN, Corio C, Leondaridis L, Tomlinson G, Dutson D, Kerber R, Amos CI, Strong LC, Berry DA, Euhus DM, Parmigiani G.  Characterization of BRCA1 and BRCA2 Mutations in a Large US Sample.  Journal of Clinical Oncology, February 2006, 24(6):863-71. 

Cler L, Bu D-w, Lewis C, Euhus DM. A comparison of five methods for extracting DNA from paucicellular clinical samples.  Molecular and Cellular Probes, March 2006. 

Euhus DM.  Breast Cancer Prevention in the 21st Century -- Defining the Challenge. The Breast Journal, March/April 2006, 12(2):97-98. 

Lewis C, Herbert B-S, Bu D, Halloway S, Beck A, Shadeo A, Zhang C, Ashfaq R, Shay JW, Euhus DM.  Telomerase immortalization of human mammary epithelial cells derived from a BRCA2 mutation carrier.  Breast Cancer Research and Treatment, March 16, 2006. 

Zhang C, Naftalis E, Euhus DM. Carcinogen-induced DNA Double Strand Break Repair in Sporadic Breast Cancer.  Journal of Surgical Research 2006,  April 2006. 

Bu D, Tomlinson G, Lewis CM, Zhang C, Kildebeck E, Euhus DM.  An Intronic Polymorphism Associated with Increased XRCC1 Expression, Reduced Apoptosis and Familial Breast Cancer.  Breast Cancer Research and Treatment 2006,  April 2006.

If you would like additional information, please contact Dr. Brekken or Dr. Euhus.

Rolf A. Brekken, Ph.D.
Office:  214/648 5151
Lab:      214/648 7345
Fax:      214/648 4940
rolf.brekken@utsouthwestern.edu

David M. Euhus, M.D.
Office: 214/648-6467
Lab:     214/648-4975
Fax:     214/648-7965
david.euhus@utsouthwestern.edu