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