DF/HCC Program Affiliation

Breast Cancer
Cancer Cell Biology

Research Abstract

The Brugge laboratory is investigating the cellular processes and pathways that are involved in normal morphogenesis of epithelial tissues and the initiation and progression of epithelial tumors. Currently, most of our studies involve investigations relating to breast cancer. One of the major approaches that we use to investigate these processes involves culturing breast epithelial cells reconstituted basement membrane gels which allows the cells to organize into 3-dimensional structures that resemble the hollow, spherical glandular units of the breast. This culture system allows us to model events that control the proliferation, survival and migration of normal epithelial cells, to identify cellular genes that allow escape from these controls and induce phenotypic changes resembling those associated with tumor progression, and to elucidate the mechanisms responsible for these events.

One of the major focuses of this project involves studies of cell death processes that are critically involved in the formation of a lumen in the spheroid, gland-like breast epithelial structures and how oncogenes escape these death processes to allow filling of the luminal space. One of the hallmarks of early-stage carcinomas filling of the lumen. We have found that multiple processes contribute to the death or clearance of cells from the lumen, including apoptosis, metabolic impairment and autophagy, and intercalation into the outer cell monolayer. Our studies indicate that the induction of apoptosis and autophagy may be a consequence of lack of matrix protein deposition by the inner cells of the acinar structures, so we are investigating how matrix proteins regulate apoptosis and metabolic activity and how oncogenes suppress apoptosis and allow rescue from metabolic impairment. Lastly, we have identified a novel, non-apoptotic mechanism of cell death that involves invasion of one cell into the other, followed by lysosomal degradation of the invading cell. We are exploring the role of this process in tumor surveillance and other physiological processes.

Another major focus is on cellular pathways that regulate the aberrant migration and invasion of tumor cells. We are carrying out siRNA screens to identify genes that inhibit or enhance cell migration and invasion, investigating the mechanisms responsible for these events, and establishing whether these pathways are involved in invasion in vivo.

Other studies involve investigations of cellular pathways that control normal differentiation of breast epithelial cells in order to understand the contribution of factors and pathways that regulate these events in tumorigenesis.

Publications

• Muthuswamy SK, Gilman M, Brugge JS.Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers.Mol Cell Biol 1999 Oct;19(10):6845-57.
  10490623
• Miranti CK, Ohno S, Brugge JS.Protein kinase C regulates integrin-induced activation of the extracellular regulated kinase pathway upstream of Shc.J Biol Chem 1999 Apr 9;274(15):10571-81.
  10187852
• Melani M, Simpson KJ, Brugge JS, Montell D.Regulation of cell adhesion and collective cell migration by hindsight and its human homolog RREB1.Curr Biol 2008 Apr 8;18(7):532-7.
  18394891
• Mailleux AA, Overholtzer M, Brugge JS.[Entosis, a cell death process related to cell cannibalism between tumor cells].Med Sci (Paris) 2008 Mar;24(3):246-8.
  18334170
• Mailleux AA, Overholtzer M, Brugge JS.Lumen formation during mammary epithelial morphogenesis: insights from in vitro and in vivo models.Cell Cycle 2008 Jan;7(1):57-62.
  18196964
• Tamimi RM, Brugge JS, Freedman ML, Miron A, Iglehart JD, Colditz GA, Hankinson SE.Circulating colony stimulating factor-1 and breast cancer risk.Cancer Res 2008 Jan 1;68(1):18-21.
  18172291
• Schafer ZT, Brugge JS.IL-6 involvement in epithelial cancers.J Clin Invest 2007 Dec;117(12):3660-3.
  18060028
• Overholtzer M, Mailleux AA, Mouneimne G, Normand G, Schnitt SJ, King RW, Cibas ES, Brugge JS.A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion.Cell 2007 Nov 30;131(5):966-79.
  18045538
• Fischbach C, Chen R, Matsumoto T, Schmelzle T, Brugge JS, Polverini PJ, Mooney DJ.Engineering tumors with 3D scaffolds.Nat Methods 2007 Oct;4(10):855-60.
  17767164
• Mouneimne G, Brugge JS.Tensins: a new switch in cell migration.Dev Cell 2007 Sep;13(3):317-9.
  17765673
• Brugge J, Hung MC, Mills GB.A new mutational AKTivation in the PI3K pathway.Cancer Cell 2007 Aug;12(2):104-7.
  17692802
• Miller-Jensen K, Janes KA, Brugge JS, Lauffenburger DA.Common effector processing mediates cell-specific responses to stimuli.Nature 2007 Aug 2;448(7153):604-8.
  17637676
• Schmelzle T, Mailleux AA, Overholtzer M, Carroll JS, Solimini NL, Lightcap ES, Veiby OP, Brugge JS.Functional role and oncogene-regulated expression of the BH3-only factor Bmf in mammary epithelial anoikis and morphogenesis.Proc Natl Acad Sci U S A 2007 M
  17360431
• Carroll DK, Brugge JS, Attardi LD.p63, cell adhesion and survival.Cell Cycle 2007 Feb;6(3):255-61.
  17297292
• Mailleux AA, Overholtzer M, Schmelzle T, Bouillet P, Strasser A, Brugge JS.BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanisms.Dev Cell 2007 Feb;12(2):221-34.
  17276340
• Walker SJ, Brugge JS.SePARating polarity and proliferation in ErbB2 oncogenesis.Nat Cell Biol 2006 Nov;8(11):1220-2.
  17077856
• Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA.Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.Proc Natl Acad Sci U S A 2006 Aug 15;103(33):12405-10.
  16894141
• Carroll DK, Carroll JS, Leong CO, Cheng F, Brown M, Mills AA, Brugge JS, Ellisen LW.p63 regulates an adhesion programme and cell survival in epithelial cells.Nat Cell Biol 2006 Jun;8(6):551-61.
  16715076
• Wilsbacher JL, Moores SL, Brugge JS.An active form of Vav1 induces migration of mammary epithelial cells by stimulating secretion of an epidermal growth factor receptor ligand.Cell Commun Signal 2006 May 18;4(1):5.
  16709244
• Witt AE, Hines LM, Collins NL, Hu Y, Gunawardane RN, Moreira D, Raphael J, Jepson D, Koundinya M, Rolfs A, Taron B, Isakoff SJ, Brugge JS, LaBaer J.Functional proteomics approach to investigate the biological activities of cDNAs implicated in breast cance
  16512675
• Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N, Natesan S, Brugge JS.Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition.J Cell Biol 2005 Dec 19;171(6):1023-34.
  16365168
• Gunawardane RN, Sgroi DC, Wrobel CN, Koh E, Daley GQ, Brugge JS.Novel role for PDEF in epithelial cell migration and invasion.Cancer Res 2005 Dec 15;65(24):11572-80.
  16357167
• Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, Cantley LC, Brugge JS.Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells.Cancer Res 2005 Dec 1;65(23):10992-1000.
  16322248
• Debnath J, Brugge JS.Modelling glandular epithelial cancers in three-dimensional cultures.Nat Rev Cancer 2005 Sep;5(9):675-88.
  16148884
• Yan SR, Joseph RR, Rosen K, Reginato MJ, Jackson A, Allaire N, Brugge JS, Jobin C, Stadnyk AW.Activation of NF-kappaB following detachment delays apoptosis in intestinal epithelial cells.Oncogene 2005 Sep 29;24(43):6482-91.
  16007176
• Collins NL, Reginato MJ, Paulus JK, Sgroi DC, Labaer J, Brugge JS.G1/S cell cycle arrest provides anoikis resistance through Erk-mediated Bim suppression.Mol Cell Biol 2005 Jun;25(12):5282-91.
  15923641
• Reginato MJ, Mills KR, Becker EB, Lynch DK, Bonni A, Muthuswamy SK, Brugge JS.Bim regulation of lumen formation in cultured mammary epithelial acini is targeted by oncogenes.Mol Cell Biol 2005 Jun;25(11):4591-601.
  15899862
• Cowan CW, Shao YR, Sahin M, Shamah SM, Lin MZ, Greer PL, Gao S, Griffith EC, Brugge JS, Greenberg ME.Vav family GEFs link activated Ephs to endocytosis and axon guidance.Neuron 2005 Apr 21;46(2):205-17.
  15848800
• Ma XJ, Wang Z, Ryan PD, Isakoff SJ, Barmettler A, Fuller A, Muir B, Mohapatra G, Salunga R, Tuggle JT, Tran Y, Tran D, Tassin A, Amon P, Wang W, Wang W, Enright E, Stecker K, Estepa-Sabal E, Smith B, Younger J, Balis U, Michaelson J, Bhan A, Habin K, Baer
  15193263
• Martin SS, Ridgeway AG, Pinkas J, Lu Y, Reginato MJ, Koh EY, Michelman M, Daley GQ, Brugge JS, Leder P.A cytoskeleton-based functional genetic screen identifies Bcl-xL as an enhancer of metastasis, but not primary tumor growth.Oncogene 2004 Jun 3;23(26):4
  15064711
• Mills KR, Reginato M, Debnath J, Queenan B, Brugge JS.Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro.Proc Natl Acad Sci U S A 2004 Mar 9;101(10):3438-43.
  14993595
• Seton-Rogers SE, Lu Y, Hines LM, Koundinya M, LaBaer J, Muthuswamy SK, Brugge JS.Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells.Proc Natl Acad Sci U S A 2004 Feb 3;1
  14739340
• Fujikawa K, Miletic AV, Alt FW, Faccio R, Brown T, Hoog J, Fredericks J, Nishi S, Mildiner S, Moores SL, Brugge J, Rosen FS, Swat W.Vav1/2/3-null mice define an essential role for Vav family proteins in lymphocyte development and activation but a differen
  14623913
• Debnath J, Walker SJ, Brugge JS.Akt activation disrupts mammary acinar architecture and enhances proliferation in an mTOR-dependent manner.J Cell Biol 2003 Oct 27;163(2):315-26.
  14568991
• Gozani O, Karuman P, Jones DR, Ivanov D, Cha J, Lugovskoy AA, Baird CL, Zhu H, Field SJ, Lessnick SL, Villasenor J, Mehrotra B, Chen J, Rao VR, Brugge JS, Ferguson CG, Payrastre B, Myszka DG, Cantley LC, Wagner G, Divecha N, Prestwich GD, Yuan J.The PHD f
  12859901
• Reginato MJ, Mills KR, Paulus JK, Lynch DK, Sgroi DC, Debnath J, Muthuswamy SK, Brugge JS.Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis.Nat Cell Biol 2003 Aug;5(8):733-40.
  12844146
• Debnath J, Muthuswamy SK, Brugge JS.Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures.Methods 2003 Jul;30(3):256-68.
  12798140
• Debnath J, Mills KR, Collins NL, Reginato MJ, Muthuswamy SK, Brugge JS.The role of apoptosis in creating and maintaining luminal space within normal and oncogene-expressing mammary acini.Cell 2002 Oct 4;111(1):29-40.
  12372298
• Miranti CK, Brugge JS.Sensing the environment: a historical perspective on integrin signal transduction.Nat Cell Biol 2002 Apr;4(4):E83-90.
  11944041
• Muthuswamy SK, Li D, Lelievre S, Bissell MJ, Brugge JS.ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini.Nat Cell Biol 2001 Sep;3(9):785-92.
  11533657
• Clark EA, King WG, Brugge JS, Symons M, Hynes RO.Integrin-mediated signals regulated by members of the rho family of GTPases.J Cell Biol 1998 Jul 27;142(2):573-86.
  9679153
• Thomas SM, Brugge JS.Cellular functions regulated by Src family kinases.Annu Rev Cell Dev Biol 1997;13:513-609.
  9442882
• Gao J, Zoller KE, Ginsberg MH, Brugge JS, Shattil SJ.Regulation of the pp72syk protein tyrosine kinase by platelet integrin alpha IIb beta 3.EMBO J 1997 Nov 3;16(21):6414-25.
  9351824
• King WG, Mattaliano MD, Chan TO, Tsichlis PN, Brugge JS.Phosphatidylinositol 3-kinase is required for integrin-stimulated AKT and Raf-1/mitogen-activated protein kinase pathway activation.Mol Cell Biol 1997 Aug;17(8):4406-18.
  9234699
• Zoller KE, MacNeil IA, Brugge JS.Protein tyrosine kinases Syk and ZAP-70 display distinct requirements for Src family kinases in immune response receptor signal transduction.J Immunol 1997 Feb 15;158(4):1650-9.
  9029101
• Bolen JB, Brugge JS.Leukocyte protein tyrosine kinases: potential targets for drug discovery.Annu Rev Immunol 1997;15:371-404.
  9143693
• Cichowski K, Brugge JS, Brass LF.Thrombin receptor activation and integrin engagement stimulate tyrosine phosphorylation of the proto-oncogene product, p95vav, in platelets.J Biol Chem 1996 Mar 29;271(13):7544-50.
  8631786
• Rusanescu G, Qi H, Thomas SM, Brugge JS, Halegoua S.Calcium influx induces neurite growth through a Src-Ras signaling cassette.Neuron 1995 Dec;15(6):1415-25.
  8845164
• Rickles RJ, Botfield MC, Zhou XM, Henry PA, Brugge JS, Zoller MJ.Phage display selection of ligand residues important for Src homology 3 domain binding specificity.Proc Natl Acad Sci U S A 1995 Nov 21;92(24):10909-13.
  7479908
• Weng Z, Rickles RJ, Feng S, Richard S, Shaw AS, Schreiber SL, Brugge JS.Structure-function analysis of SH3 domains: SH3 binding specificity altered by single amino acid substitutions.Mol Cell Biol 1995 Oct;15(10):5627-34.
  7565714
• Mukhopadhyay D, Tsiokas L, Zhou XM, Foster D, Brugge JS, Sukhatme VP.Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation.Nature 1995 Jun 15;375(6532):577-81.
  7540725
• Shiue L, Zoller MJ, Brugge JS.Syk is activated by phosphotyrosine-containing peptides representing the tyrosine-based activation motifs of the high affinity receptor for IgE.J Biol Chem 1995 May 5;270(18):10498-502.
  7537732
• Rivera VM, Brugge JS.Clustering of Syk is sufficient to induce tyrosine phosphorylation and release of allergic mediators from rat basophilic leukemia cells.Mol Cell Biol 1995 Mar;15(3):1582-90.
  7532280
• Rickles RJ, Botfield MC, Weng Z, Taylor JA, Green OM, Brugge JS, Zoller MJ.Identification of Src, Fyn, Lyn, PI3K and Abl SH3 domain ligands using phage display libraries.EMBO J 1994 Dec 1;13(23):5598-604.
  7988556
• Clark EA, Shattil SJ, Brugge JS.Regulation of protein tyrosine kinases in platelets.Trends Biochem Sci 1994 Nov;19(11):464-9.
  7855888
• Clark EA, Trikha M, Markland FS, Brugge JS.Structurally distinct disintegrins contortrostatin and multisquamatin differentially regulate platelet tyrosine phosphorylation.J Biol Chem 1994 Sep 2;269(35):21940-3.
  7520909
• Shattil SJ, Haimovich B, Cunningham M, Lipfert L, Parsons JT, Ginsberg MH, Brugge JS.Tyrosine phosphorylation of pp125FAK in platelets requires coordinated signaling through integrin and agonist receptors.J Biol Chem 1994 May 20;269(20):14738-45.
  7514181
• Thomas JE, Aguzzi A, Soriano P, Wagner EF, Brugge JS.Induction of tumor formation and cell transformation by polyoma middle T antigen in the absence of Src.Oncogene 1993 Sep;8(9):2521-9.
  7689725
• Weng Z, Taylor JA, Turner CE, Brugge JS, Seidel-Dugan C.Detection of Src homology 3-binding proteins, including paxillin, in normal and v-Src-transformed Balb/c 3T3 cells.J Biol Chem 1993 Jul 15;268(20):14956-63.
  8325872
• Huang MM, Lipfert L, Cunningham M, Brugge JS, Ginsberg MH, Shattil SJ.Adhesive ligand binding to integrin alpha IIb beta 3 stimulates tyrosine phosphorylation of novel protein substrates before phosphorylation of pp125FAK.J Cell Biol 1993 Jul;122(2):473-8
  7686553
• Brugge JS.New intracellular targets for therapeutic drug design.Science 1993 May 14;260(5110):918-9.
  8388123
• Clark EA, Brugge JS.Redistribution of activated pp60c-src to integrin-dependent cytoskeletal complexes in thrombin-stimulated platelets.Mol Cell Biol 1993 Mar;13(3):1863-71.
  7680100
• Yu H, Rosen MK, Shin TB, Seidel-Dugan C, Brugge JS, Schreiber SL.Solution structure of the SH3 domain of Src and identification of its ligand-binding site.Science 1992 Dec 4;258(5088):1665-8.
  1280858
• Lipfert L, Haimovich B, Schaller MD, Cobb BS, Parsons JT, Brugge JS.Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets.J Cell Biol 1992 Nov;119(4):905-12.
  1385445
• Thomas SM, DeMarco M, D'Arcangelo G, Halegoua S, Brugge JS.Ras is essential for nerve growth factor- and phorbol ester-induced tyrosine phosphorylation of MAP kinases.Cell 1992 Mar 20;68(6):1031-40.
  1312392