DF/HCC Program Affiliation

Gastrointestinal Malignancies
Breast Cancer
Cancer Genetics
Prostate Cancer

Research Abstract

While the selective and irreversible destruction of a given protein occurs through its ubiquitination, this enzymatic process can be reversed by de-ubiquitinating enzymes .
We have been interested for several years in this family of enzymes and recently discovered that one such enzyme, USP2a, is androgen responsive, is overexpressed in prostate tumors, and most importantly, regulates the stability of fatty acid synthase (FAS), essential for tumor cell survival. Since inhibition of this enzyme as well as of its substrate, fatty acid synthase, results in significant prostate cancer cell death, these are both important therapeutic targets in this disease. Dr. Loda's laboratory is focused on the role played by these proteins in prostate carcinogenesis and in the development of USP2a and FAS inhibitors that may be used in the clinic.

The regulation of replication in human cells is complex. Several genes are involved, either favoring or inhibiting progression of cellular division. Targeted protein degradation by the ubiquitin-proteasome pathway plays a vital role in monitoring the abundance of several proteins involved in cell cycle regulation. We have shown that loss of p27, a powerful inhibitor of cyclin-dependent kinases, has been associated with aggressive behavior in a variety of tumors, including prostate cancer. Our laboratory has also demonstrated, for the first time, that targeted destruction of p27 is a mechanism utilized by cancer cells to become more aggressive. Furthermore, we have shown that the ubiquitin ligase responsible for the degradation of p27, Skp2 is overexpressed in estrogen receptor-negative human breast cancers. We focus our research efforts on the dysregulation of p27 in cancer utilizing cell line and animal models as well as human tumors.

Publications

• Baumgart E, Cohen MS, Neto BS, Jacobs MA, Wotkowicz C, Rieger-Christ KM, Biolo A, Zeheb R, Loda M, Libertino JA, Summerhayes IC.Identification and prognostic significance of an epithelial-mesenchymal transition expression profile in human bladder tumors.C
  17363521
• Byers RJ, Di Vizio D, O'connell F, Tholouli E, Levenson RM, Gossard K, Twomey D, Yang Y, Benedettini E, Rose J, Ligon KL, Finn SP, Golub TR, Loda M.Semiautomated multiplexed quantum dot-based in situ hybridization and spectral deconvolution.J Mol Diagn 20
  17251332
• Priolo C, Tang D, Brahamandan M, Benassi B, Sicinska E, Ogino S, Farsetti A, Porrello A, Finn S, Zimmermann J, Febbo P, Loda M.The Isopeptidase USP2a Protects Human Prostate Cancer from Apoptosis.Cancer Res 2006 Sep 1;66(17):8625-32.
  16951176
• Tholouli E, Hoyland JA, Di Vizio D, O'Connell F, Macdermott SA, Twomey D, Levenson R, Yin JA, Golub TR, Loda M, Byers R.Imaging of multiple mRNA targets using quantum dot based in situ hybridization and spectral deconvolution in clinical biopsies.Biochem
  16893519
• Ogino S, Kawasaki T, Kirkner G, Ogawa A, Dorfman I, Loda M, Fuchs C.Down-regulation of p21 (CDKN1A/CIP1) is inversely associated with microsatellite instability and CpG island methylator phenotype (CIMP) in colorectal cancer.J Pathol 2006 Jul 19.
  16850502
• Berger R, Lin DI, Nieto M, Sicinska E, Garraway LA, Adams H, Signoretti S, Hahn WC, Loda M.Androgen-dependent regulation of Her-2/neu in prostate cancer cells.Cancer Res 2006 Jun 1;66(11):5723-8.
  16740710
• Nanni S, Priolo C, Grasselli A, D'Eletto M, Merola R, Moretti F, Gallucci M, De Carli P, Sentinelli S, Cianciulli AM, Mottolese M, Carlini P, Arcelli D, Helmer-Citterich M, Gaetano C, Loda M, Pontecorvi A, Bacchetti S, Sacchi A, Farsetti A.Epithelial-rest
  16513839
• Signoretti S, Pires MM, Lindauer M, Horner JW, Grisanzio C, Dhar S, Majumder P, McKeon F, Kantoff PW, Sellers WR, Loda M.p63 regulates commitment to the prostate cell lineage.Proc Natl Acad Sci U S A 2005 Aug 9;102(32):11355-60.
  16051706
• Graner E, Tang D, Rossi S, Baron A, Migita T, Weinstein LJ, Lechpammer M, Huesken D, Zimmermann J, Signoretti S, Loda M.The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer.Cancer Cell 2004 Mar;5(3):253-61.
  15050917
• Baron A, Migita T, Tang D, Loda M.Fatty acid synthase: a metabolic oncogene in prostate cancer?.J Cell Biochem 2004 Jan 1;91(1):47-53.
  14689581
• Rossi S, Graner E, Febbo P, Weinstein L, Bhattacharya N, Onody T, Bubley G, Balk S, Loda M.Fatty acid synthase expression defines distinct molecular signatures in prostate cancer.Mol Cancer Res 2003 Aug;1(10):707-15.
  12939396
• Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti S, Loda M, Roberts TM, Zhao JJ.Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis.Nature;454:776-9.
• Laios A, Toole SO, Flavin R, Martin C, Kelly L, Ring M, Finn SP, Barret C, Loda M, Gleeson N, Arcy TD, McGuinness EP, Sheils O, Sheppard B, Leary JO.Potential role of miR-9 and miR-223 in recurrent ovarian cancer.Mol Cancer 2008 Apr 28;7(1):35.
  18442408
• Flavin RJ, Smyth PC, Finn SP, Laios A, O'Toole SA, Barrett C, Ring M, Denning KM, Li J, Aherne ST, Aziz NA, Alhadi A, Sheppard BL, Loda M, Martin C, Sheils OM, O'Leary JJ.Altered eIF6 and Dicer expression is associated with clinicopathological features in
  18327211
• Swain RS, Tihan T, Horvai AE, Di Vizio D, Loda M, Burger PC, Scheithauer BW, Kim GE.Inflammatory myofibroblastic tumor of the central nervous system and its relationship to inflammatory pseudotumor.Hum Pathol 2008 Mar;39(3):410-9.
  18261625
• Febbo PG, Mulligan MG, Slonina DA, Stegmeir K, Di Vizio D, Martinez PR, Loda M, Taylor SC.Literature Lab: a method of automated literature interrogation to infer biology from microarray analysis.BMC Genomics 2007;8:461.
  18088408
• Kawasaki T, Ohnishi M, Suemoto Y, Kirkner GJ, Liu Z, Yamamoto H, Loda M, Fuchs CS, Ogino S.WRN promoter methylation possibly connects mucinous differentiation, microsatellite instability and CpG island methylator phenotype in colorectal cancer.Mod Pathol
  18084250
• Hittelman A, Sridharan S, Roy R, Fridlyand J, Loda M, Collins C, Paris PL.Evaluation of whole genome amplification protocols for array and oligonucleotide CGH.Diagn Mol Pathol 2007 Dec;16(4):198-206.
  18043282
• Xu Q, Majumder PK, Ross K, Shim Y, Golub TR, Loda M, Sellers WR.Identification of prostate cancer modifier pathways using parental strain expression mapping.Proc Natl Acad Sci U S A 2007 Nov 6;104(45):17771-6.
  17978178
• Silva Neto B, Smith GL, Mandeville JA, Vanni AJ, Wotkowicz C, Rieger-Christ KM, Baumgart E, Jacobs MA, Cohen MS, Zeheb R, Loda M, Libertino JA, Summerhayes IC.Prognostic significance of altered p120 ctn expression in bladder cancer.BJU Int 2008 Mar;101(6)
  17922855
• Di Vizio D, Sotgia F, Williams TM, Hassan GS, Capozza F, Frank PG, Pestell RG, Loda M, Freeman MR, Lisanti MP.Caveolin-1 is required for the upregulation of fatty acid synthase (FASN), a tumor promoter, during prostate cancer progression.Cancer Biol Ther
  17786030
• Wang F, Wang L, Briggs C, Sicinska E, Gaston SM, Mamon H, Kulke MH, Zamponi R, Loda M, Maher E, Ogino S, Fuchs CS, Li J, Hader C, Makrigiorgos GM.DNA degradation test predicts success in whole-genome amplification from diverse clinical samples.J Mol Diagn
  17690213
• Ogino S, Kawasaki T, Kirkner GJ, Kraft P, Loda M, Fuchs CS.Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample.J Mol Diagn 2007 Jul;9(3):305-14.
  17591929
• Vivanco I, Palaskas N, Tran C, Finn SP, Getz G, Kennedy NJ, Jiao J, Rose J, Xie W, Loda M, Golub T, Mellinghoff IK, Davis RJ, Wu H, Sawyers CL.Identification of the JNK signaling pathway as a functional target of the tumor suppressor PTEN.Cancer Cell 2007
  17560336
• Ogino S, Kawasaki T, Kirkner GJ, Kraft P, Loda M, Fuchs CS.Evaluation of Markers for CpG Island Methylator Phenotype (CIMP) in Colorectal Cancer by a Large Population-Based Sample.J Mol Diagn 2007 May 3.
  17478565
• Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, Wang M, Feng W, Zander T, Macconnaill LE, Lee JC, Nicoletti R, Hatton C, Goyette M, Girard L, Majmudar K, Ziaugra L, Wong KK, Gabriel S, Beroukhim R, Peyton M, Barretina J, Dutt A, Emery
  17392811
• Ogino S, Meyerhardt JA, Kawasaki T, Clark JW, Ryan DP, Kulke MH, Enzinger PC, Wolpin BM, Loda M, Fuchs CS.CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma.Virchows Ar
  17372756
• Ogino S, Kawasaki T, Ogawa A, Kirkner GJ, Loda M, Fuchs CS.Fatty acid synthase overexpression in colorectal cancer is associated with microsatellite instability, independent of CpG island methylator phenotype.Hum Pathol 2007 Mar 9.
  17350669
• Nieto M, Finn S, Loda M, Hahn WC.Prostate cancer: Re-focusing on androgen receptor signaling.Int J Biochem Cell Biol 2007 Jan 20.
  17321194
• Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, Wang M, Feng W, Zander T, MacConaill L, Lee JC, Nicoletti R, Hatton C, Goyette M, Girard L, Majmudar K, Ziaugra L, Wong KK, Gabriel S, Beroukhim R, Peyton M, Barretina J, Dutt A, Emery C,
  17293865
• Ogino S, Kawasaki T, Ogawa A, Kirkner GJ, Loda M, Fuchs CS.TGFBR2 mutation is correlated with CpG island methylator phenotype in microsatellite instability-high colorectal cancer.Hum Pathol 2007 Jan 31.
  17270239
• Ogino S, Kawasaki T, Ogawa A, Kirkner GJ, Loda M, Fuchs CS.Cytoplasmic localization of p27 (cyclin-dependent kinase inhibitor 1B/KIP1) in colorectal cancer: inverse correlations with nuclear p27 loss, microsatellite instability, and CpG island methylator
  17239930
• Ogino S, Kawasaki T, Kirkner GJ, Yamaji T, Loda M, Fuchs CS.Loss of nuclear p27 (CDKN1B/KIP1) in colorectal cancer is correlated with microsatellite instability and CIMP.Mod Pathol 2007 Jan;20(1):15-22.
  17086168
• Ogino S, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS.CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations.J Mol Diagn 2006 Nov;8(5):582-8.
  17065427
• De Marzo AM, Platz EA, Epstein JI, Ali T, Billis A, Chan TY, Cheng L, Datta M, Egevad L, Ertoy-Baydar D, Farre X, Fine SW, Iczkowski KA, Ittmann M, Knudsen BS, Loda M, Lopez-Beltran A, Magi-Galluzzi C, Mikuz G, Montironi R, Pikarsky E, Pizov G, Rubin MA,
  17001160
• Ogino S, Odze RD, Kawasaki T, Brahmandam M, Kirkner GJ, Laird PW, Loda M, Fuchs CS.Correlation of pathologic features with CpG island methylator phenotype (CIMP) by quantitative DNA methylation analysis in colorectal carcinoma.Am J Surg Pathol 2006 Sep;30
  16931963
• Gizatullin F, Yao Y, Kung V, Harding MW, Loda M, Shapiro GI.The Aurora Kinase Inhibitor VX-680 Induces Endoreduplication and Apoptosis Preferentially in Cells with Compromised p53-Dependent Postmitotic Checkpoint Function.Cancer Res 2006 Aug 1;66(15):7668
  16885368
• Oh WK, Hayes J, Evan C, Manola J, George DJ, Waldron H, Donovan M, Varner J, Orechia J, Katcher B, Lu D, Nevins A, Wright RL, Tormey L, Talcott J, Rubin MA, Loda M, Sellers WR, Richie JP, Kantoff PW, Weeks J.Development of an integrated prostate cancer re
  16859581
• Ogino S, Brahmandam M, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS.Combined analysis of COX-2 and p53 expressions reveals synergistic inverse correlations with microsatellite instability and CpG island methylator phenotype in colorectal cancer.Neoplasia 2006
  16820091
• Signoretti S, Loda M.Prostate stem cells: From development to cancer.Semin Cancer Biol 2006 May 10.
  16781871
• Ogino S, Brahmandam M, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS.Epigenetic profiling of synchronous colorectal neoplasias by quantitative DNA methylation analysis.Mod Pathol 2006 May 12.
  16699497
• Rossi S, Ou W, Tang D, Bhattacharya N, Dei Tos A, Fletcher J, Loda M.Gastrointestinal stromal tumours overexpress fatty acid synthase.J Pathol 2006 Mar 31.
  16583360
• Febbo PG, Thorner A, Rubin MA, Loda M, Kantoff PW, Oh WK, Golub T, George D.Application of oligonucleotide microarrays to assess the biological effects of neoadjuvant imatinib mesylate treatment for localized prostate cancer.Clin Cancer Res 2006 Jan 1;12(
  16397037
• Signoretti S, Loda M.Defining cell lineages in the prostate epithelium.Cell Cycle 2006 Jan;5(2):138-41.
  16357539
• Zhao JJ, Liu Z, Wang L, Shin E, Loda MF, Roberts TM.The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells.Proc Natl Acad Sci U S A 2005 Dec 20;102(51):18443-8.
  16339315
• Luo J, Sobkiw CL, Logsdon NM, Watt JM, Signoretti S, O'Connell F, Shin E, Shim Y, Pao L, Neel BG, Depinho RA, Loda M, Cantley LC.Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice by the p85 regulatory subunits of phosphoinositide
  16006513
• Lechpammer M, Xu X, Ellis FH, Bhattacharaya N, Shapiro GI, Loda M.Flavopiridol reduces malignant transformation of the esophageal mucosa in p27 knockout mice.Oncogene 2005 Mar 3;24(10):1683-8.
  15674336
• Berger R, Febbo PG, Majumder PK, Zhao JJ, Mukherjee S, Signoretti S, Campbell KT, Sellers WR, Roberts TM, Loda M, Golub TR, Hahn WC.Androgen-induced differentiation and tumorigenicity of human prostate epithelial cells.Cancer Res 2004 Dec 15;64(24):8867-7
  15604246
• Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR.mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-d
  15156201
• Lieberfarb ME, Lin M, Lechpammer M, Li C, Tanenbaum DM, Febbo PG, Wright RL, Shim J, Kantoff PW, Loda M, Meyerson M, Sellers WR.Genome-wide loss of heterozygosity analysis from laser capture microdissected prostate cancer using single nucleotide polymorph
  12941794
• Sellers WR, Loda M.The EZH2 polycomb transcriptional repressor--a marker or mover of metastatic prostate cancer?.Cancer Cell 2002 Nov;2(5):349-50.
  12450788
• Signoretti S, Di Marcotullio L, Richardson A, Ramaswamy S, Isaac B, Rue M, Monti F, Loda M, Pagano M.Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer.J Clin Invest 2002 Sep;110(5):633-41.
  12208864
• Singh D, Febbo PG, Ross K, Jackson DG, Manola J, Ladd C, Tamayo P, Renshaw AA, D'Amico AV, Richie JP, Lander ES, Loda M, Kantoff PW, Golub TR, Sellers WR.Gene expression correlates of clinical prostate cancer behavior.Cancer Cell 2002 Mar;1(2):203-9.
  12086878
• DeSalle LM, Latres E, Lin D, Graner E, Montagnoli A, Baker RT, Pagano M, Loda M.The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein.Oncogene 2001 Sep 6;20(39):5538-42.
  11571652
• Waltregny D, Leav I, Signoretti S, Soung P, Lin D, Merk F, Adams JY, Bhattacharya N, Cirenei N, Loda M.Androgen-driven prostate epithelial cell proliferation and differentiation in vivo involve the regulation of p27.Mol Endocrinol 2001 May;15(5):765-82.
  11328857
• Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M.Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas.Nat Med 1997 Feb;3(2):231-4.
  9018245