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Journal of Mammary Gland Biology and Neoplasia

Published in:

01-06-2010

Cell Polarity in Motion: Redefining Mammary Tissue Organization Through EMT and Cell Polarity Transitions

Authors: Nathan J. Godde, Ryan C. Galea, Imogen A. Elsum, Patrick O. Humbert

Published in: Journal of Mammary Gland Biology and Neoplasia | Issue 2/2010

Abstract

Epithelial to mesenchymal transition (EMT) and its reversion via mesenchymal to epithelial transition (MET), represent a stepwise cycle of epithelial plasticity that allows for normal tissue remodelling and diversification during development. In particular, epithelial-mesenchymal plasticity is central to many aspects of mammary development and has been proposed to be a key process in breast cancer progression. Such epithelial-mesenchymal plasticity requires complex cellular reprogramming to orchestrate a change in cell shape to an alternate morphology more conducive to migration. During this process, epithelial characteristics, including apical-basal polarity and specialised cell-cell junctions are lost and mesenchymal properties, such as a front-rear polarity associated with weak cell-cell contacts, increased motility, resistance to apoptosis and invasiveness are gained. The ability of epithelial cells to undergo transitions through cell polarity states is a central feature of epithelial-mesenchymal plasticity. These cell polarity states comprise a set of distinct asymmetric distributions of cellular constituents that are fashioned to allow specialized cellular functions, such as the regulated homeostasis of molecules across epithelial barriers, cell migration or cell diversification via asymmetric cell divisions. Each polarity state is engineered using a molecular toolbox that is highly conserved between organisms and cell types which can direct the initiation, establishment and continued maintenance of each asymmetry. Here we discuss how EMT pathways target cell polarity mediators, and how this EMT-dependent change in polarity states impact on the various stages of breast cancer. Emerging evidence places cell polarity at the interface of proliferation and morphology control and as such the changing dynamics within polarity networks play a critical role in normal mammary gland development and breast cancer progression.

Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009;139(5):871–90.PubMed

Lanigan F, O’Connor D, Martin F, Gallagher WM. Molecular links between mammary gland development and breast cancer. Cell Mol Life Sci. 2007;64(24):3159–84.PubMed

Tomaskovic-Crook E, Thompson EW, Thiery JP. Epithelial to mesenchymal transition and breast cancer. Breast Cancer Res. 2009;11(6):213.PubMed

Russo J, Russo IH. Development of the human breast. Maturitas 2004;49(1):2–15.PubMed

Hennighausen L, Robinson GW. Signaling pathways in mammary gland development. Dev Cell. 2001;1(4):467–75.PubMed

Brennan K, Offiah G, McSherry EA, Hopkins AM. Tight junctions: a barrier to the initiation and progression of breast cancer? J Biomed Biotechnol. 2010;2010:460607.PubMed

Gumbiner BM. Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol. 2005;6(8):622–34.PubMed

Gurdon JB, Bourillot PY. Morphogen gradient interpretation. Nature 2001;413(6858):797–803.PubMed

Kass L, Erler JT, Dembo M, Weaver VM. Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis. Int J Biochem Cell Biol. 2007;39(11):1987–94.PubMed

10.

O’Brien LE, Jou TS, Pollack AL, Zhang Q, Hansen SH, Yurchenco P, et al. Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nat Cell Biol. 2001;3(9):831–8.PubMed

11.

Gudjonsson T, Ronnov-Jessen L, Villadsen R, Rank F, Bissell MJ, Petersen OW. Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition. J Cell Sci. 2002;115(Pt 1):39–50.PubMed

12.

Debnath J, Brugge JS. Modelling glandular epithelial cancers in three-dimensional cultures. Nat Rev Cancer. 2005;5(9):675–88.PubMed

13.

Barcellos-Hoff MH, Aggeler J, Ram TG, Bissell MJ. Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane. Development 1989;105(2):223–35.PubMed

14.

Debnath J, Muthuswamy SK, Brugge JS. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 2003;30(3):256–68.PubMed

15.

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;111(1):29–40.PubMed

16.

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;12(2):221–34.PubMed

17.

Mailleux AA, Overholtzer M, Brugge JS. Lumen formation during mammary epithelial morphogenesis: insights from in vitro and in vivo models. Cell Cycle. 2008;7(1):57–62.PubMed

18.

Humphreys RC, Krajewska M, Krnacik S, Jaeger R, Weiher H, Krajewski S, et al. Apoptosis in the terminal endbud of the murine mammary gland: a mechanism of ductal morphogenesis. Development 1996;122(12):4013–22.PubMed

19.

Reginato MJ, Muthuswamy SK. Illuminating the center: mechanisms regulating lumen formation and maintenance in mammary morphogenesis. J Mammary Gland Biol Neoplasia. 2006;11(3–4):205–11.PubMed

20.

Jechlinger M, Podsypanina K, Varmus H. Regulation of transgenes in three-dimensional cultures of primary mouse mammary cells demonstrates oncogene dependence and identifies cells that survive deinduction. Genes Dev. 2009;23(14):1677–88.PubMed

21.

Bacallao R, Antony C, Dotti C, Karsenti E, Stelzer EH, Simons K. The subcellular organization of Madin-Darby canine kidney cells during the formation of a polarized epithelium. J Cell Biol. 1989;109(6 Pt 1):2817–32.PubMed

22.

Harris TJ, Peifer M. The positioning and segregation of apical cues during epithelial polarity establishment in Drosophila. J Cell Biol. 2005;170(5):813–23.PubMed

23.

Li Z, Wang L, Hays TS, Cai Y. Dynein-mediated apical localization of crumbs transcripts is required for Crumbs activity in epithelial polarity. J Cell Biol. 2008;180(1):31–8.PubMed

24.

Dow LE, Humbert PO. Polarity regulators and the control of epithelial architecture, cell migration, and tumorigenesis. Int Rev Cytol. 2007;262:253–302.PubMed

25.

Harris TJ, Peifer M. Adherens junction-dependent and -independent steps in the establishment of epithelial cell polarity in Drosophila. J Cell Biol. 2004;167(1):135–47.PubMed

26.

Baas AF, Kuipers J, van der Wel NN, Batlle E, Koerten HK, Peters PJ, et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 2004;116(3):457–66.PubMed

27.

Ebnet K. Organization of multiprotein complexes at cell-cell junctions. Histochem Cell Biol. 2008;130(1):1–20.PubMed

28.

Nakagawa M, Fukata M, Yamaga M, Itoh N, Kaibuchi K. Recruitment and activation of Rac1 by the formation of E-cadherin-mediated cell-cell adhesion sites. J Cell Sci. 2001;114(Pt 10):1829–38.PubMed

29.

Wildenberg GA, Dohn MR, Carnahan RH, Davis MA, Lobdell NA, Settleman J, et al. p120-catenin and p190RhoGAP regulate cell-cell adhesion by coordinating antagonism between Rac and Rho. Cell 2006;127(5):1027–39.PubMed

30.

Yamada S, Nelson WJ. Localized zones of Rho and Rac activities drive initiation and expansion of epithelial cell-cell adhesion. J Cell Biol. 2007;178(3):517–27.PubMed

31.

Noren NK, Niessen CM, Gumbiner BM, Burridge K. Cadherin engagement regulates Rho family GTPases. J Biol Chem. 2001;276(36):33305–8.PubMed

32.

Gassama-Diagne A, Yu W, ter Beest M, Martin-Belmonte F, Kierbel A, Engel J, et al. Phosphatidylinositol-3, 4, 5-trisphosphate regulates the formation of the basolateral plasma membrane in epithelial cells. Nat Cell Biol. 2006;8(9):963–70.PubMed

33.

Martin-Belmonte F, Gassama A, Datta A, Yu W, Rescher U, Gerke V, et al. PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell 2007;128(2):383–97.PubMed

34.

von Stein W, Ramrath A, Grimm A, Muller-Borg M, Wodarz A. Direct association of Bazooka/PAR-3 with the lipid phosphatase PTEN reveals a link between the PAR/aPKC complex and phosphoinositide signaling. Development 2005;132(7):1675–86.

35.

Wu Y, Dowbenko D, Spencer S, Laura R, Lee J, Gu Q, et al. Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase. J Biol Chem. 2000;275(28):21477–85.PubMed

36.

Pece S, Chiariello M, Murga C, Gutkind JS. Activation of the protein kinase Akt/PKB by the formation of E-cadherin-mediated cell-cell junctions. Evidence for the association of phosphatidylinositol 3-kinase with the E-cadherin adhesion complex. J Biol Chem. 1999;274(27):19347–51.PubMed

37.

Halet G, Viard P, Carroll J. Constitutive PtdIns(3, 4, 5)P3 synthesis promotes the development and survival of early mammalian embryos. Development 2008;135(3):425–9.PubMed

38.

Kovacs EM, Ali RG, McCormack AJ, Yap AS. E-cadherin homophilic ligation directly signals through Rac and phosphatidylinositol 3-kinase to regulate adhesive contacts. J Biol Chem. 2002;277(8):6708–18.PubMed

39.

Parkinson SJ, Le Good JA, Whelan RD, Whitehead P, Parker PJ. Identification of PKCzetaII: an endogenous inhibitor of cell polarity. EMBO J. 2004;23(1):77–88.PubMed

40.

Suzuki A, Yamanaka T, Hirose T, Manabe N, Mizuno K, Shimizu M, et al. Atypical protein kinase C is involved in the evolutionarily conserved par protein complex and plays a critical role in establishing epithelia-specific junctional structures. J Cell Biol. 2001;152(6):1183–96.PubMed

41.

Itoh M, Sasaki H, Furuse M, Ozaki H, Kita T, Tsukita S. Junctional adhesion molecule (JAM) binds to PAR-3: a possible mechanism for the recruitment of PAR-3 to tight junctions. J Cell Biol. 2001;154(3):491–7.PubMed

42.

Takekuni K, Ikeda W, Fujito T, Morimoto K, Takeuchi M, Monden M, et al. Direct binding of cell polarity protein PAR-3 to cell-cell adhesion molecule nectin at neuroepithelial cells of developing mouse. J Biol Chem. 2003;278(8):5497–500.PubMed

43.

Feng W, Wu H, Chan LN, Zhang M. Par-3-mediated junctional localization of the lipid phosphatase PTEN is required for cell polarity establishment. J Biol Chem. 2008;283(34):23440–9.PubMed

44.

Wu H, Feng W, Chen J, Chan LN, Huang S, Zhang M. PDZ domains of Par-3 as potential phosphoinositide signaling integrators. Mol Cell. 2007;28(5):886–98.PubMed

45.

Feng W, Wu H, Chan LN, Zhang M. The Par-3 NTD adopts a PB1-like structure required for Par-3 oligomerization and membrane localization. EMBO J. 2007;26(11):2786–96.PubMed

46.

Mizuno K, Suzuki A, Hirose T, Kitamura K, Kutsuzawa K, Futaki M, et al. Self-association of PAR-3-mediated by the conserved N-terminal domain contributes to the development of epithelial tight junctions. J Biol Chem. 2003;278(33):31240–50.PubMed

47.

Chen X, Macara IG. Par-3 controls tight junction assembly through the Rac exchange factor Tiam1. Nat Cell Biol. 2005;7(3):262–9.PubMed

48.

Kim SH, Li Z, Sacks DB. E-cadherin-mediated cell-cell attachment activates Cdc42. J Biol Chem. 2000;275(47):36999–7005.PubMed

49.

Straight SW, Shin K, Fogg VC, Fan S, Liu CJ, Roh M, et al. Loss of PALS1 expression leads to tight junction and polarity defects. Mol Biol Cell. 2004;15(4):1981–90.PubMed

50.

Hurd TW, Gao L, Roh MH, Macara IG, Margolis B. Direct interaction of two polarity complexes implicated in epithelial tight junction assembly. Nat Cell Biol. 2003;5(2):137–42.PubMed

51.

Yamanaka T, Horikoshi Y, Suzuki A, Sugiyama Y, Kitamura K, Maniwa R, et al. PAR-6 regulates aPKC activity in a novel way and mediates cell-cell contact-induced formation of the epithelial junctional complex. Genes Cells. 2001;6(8):721–31.PubMed

52.

Lemmers C, Michel D, Lane-Guermonprez L, Delgrossi MH, Medina E, Arsanto JP, et al. CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells. Mol Biol Cell. 2004;15(3):1324–33.PubMed

53.

Kametani Y, Takeichi M. Basal-to-apical cadherin flow at cell junctions. Nat Cell Biol. 2007;9(1):92–8.PubMed

54.

Plant PJ, Fawcett JP, Lin DC, Holdorf AD, Binns K, Kulkarni S, et al. A polarity complex of mPar-6 and atypical PKC binds, phosphorylates and regulates mammalian Lgl. Nat Cell Biol. 2003;5(4):301–8.PubMed

55.

Yamanaka T, Horikoshi Y, Sugiyama Y, Ishiyama C, Suzuki A, Hirose T, et al. Mammalian Lgl forms a protein complex with PAR-6 and aPKC independently of PAR-3 to regulate epithelial cell polarity. Curr Biol. 2003;13(9):734–43.PubMed

56.

Betschinger J, Mechtler K, Knoblich JA. The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl. Nature 2003;422(6929):326–30.PubMed

57.

Humbert PO, Dow LE, Russell SM. The Scribble and Par complexes in polarity and migration: friends or foes? Trends Cell Biol. 2006;16(12):622–30.PubMed

58.

Fogg VC, Liu CJ, Margolis B. Multiple regions of Crumbs3 are required for tight junction formation in MCF10A cells. J Cell Sci. 2005;118(Pt 13):2859–69.PubMed

59.

Shin K, Straight S, Margolis B. PATJ regulates tight junction formation and polarity in mammalian epithelial cells. J Cell Biol. 2005;168(5):705–11.PubMed

60.

Qin Y, Capaldo C, Gumbiner BM, Macara IG. The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J Cell Biol. 2005;171(6):1061–71.PubMed

61.

Wang Z, Sandiford S, Wu C, Li SS. Numb regulates cell-cell adhesion and polarity in response to tyrosine kinase signalling. EMBO J. 2009;28(16):2360–73.PubMed

62.

Mostov KE, Verges M, Altschuler Y. Membrane traffic in polarized epithelial cells. Curr Opin Cell Biol. 2000;12(4):483–90.PubMed

63.

Nelson WJ. Remodeling epithelial cell organization: transitions between front-rear and apical-basal polarity. Cold Spring Harb Perspect Biol. 2009;1(1):Published online doi:10.1101/cshperspect.a000513.

64.

Lafont F, Burkhardt JK, Simons K. Involvement of microtubule motors in basolateral and apical transport in kidney cells. Nature 1994;372(6508):801–3.PubMed

65.

Jaulin F, Xue X, Rodriguez-Boulan E, Kreitzer G. Polarization-dependent selective transport to the apical membrane by KIF5B in MDCK cells. Dev Cell. 2007;13(4):511–22.PubMed

66.

Manser E, Loo TH, Koh CG, Zhao ZS, Chen XQ, Tan L, et al. PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Mol Cell. 1998;1(2):183–92.PubMed

67.

Audebert S, Navarro C, Nourry C, Chasserot-Golaz S, Lecine P, Bellaiche Y, et al. Mammalian Scribble forms a tight complex with the betaPIX exchange factor. Curr Biol. 2004;14(11):987–95.PubMed

68.

Musch A, Cohen D, Yeaman C, Nelson WJ, Rodriguez-Boulan E, Brennwald PJ. Mammalian homolog of Drosophila tumor suppressor lethal (2) giant larvae interacts with basolateral exocytic machinery in Madin-Darby canine kidney cells. Mol Biol Cell. 2002;13(1):158–68.PubMed

69.

Lehman K, Rossi G, Adamo JE, Brennwald P. Yeast homologues of tomosyn and lethal giant larvae function in exocytosis and are associated with the plasma membrane SNARE, Sec9. J Cell Biol. 1999;146(1):125–40.PubMed

70.

Klezovitch O, Fernandez TE, Tapscott SJ, Vasioukhin V. Loss of cell polarity causes severe brain dysplasia in Lgl1 knockout mice. Genes Dev. 2004;18(5):559–71.PubMed

71.

Etienne-Manneville S. Polarity proteins in migration and invasion. Oncogene 2008;27(55):6970–80.PubMed

72.

Iden S, Collard JG. Crosstalk between small GTPases and polarity proteins in cell polarization. Nat Rev Mol Cell Biol. 2008;9(11):846–59.PubMed

73.

Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, et al. Cell migration: integrating signals from front to back. Science 2003;302(5651):1704–9.PubMed

74.

Funamoto S, Meili R, Lee S, Parry L, Firtel RA. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 2002;109(5):611–23.PubMed

75.

Iijima M, Devreotes P. Tumor suppressor PTEN mediates sensing of chemoattractant gradients. Cell 2002;109(5):599–610.PubMed

76.

Merlot S, Firtel RA. Leading the way: directional sensing through phosphatidylinositol 3-kinase and other signaling pathways. J Cell Sci. 2003;116(Pt 17):3471–8.PubMed

77.

Welch HC, Coadwell WJ, Stephens LR, Hawkins PT. Phosphoinositide 3-kinase-dependent activation of Rac. FEBS Lett. 2003;546(1):93–7.PubMed

78.

Etienne-Manneville S. Cdc42-the centre of polarity. J Cell Sci. 2004;117(Pt 8):1291–300.PubMed

79.

Etienne-Manneville S, Hall A. Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCzeta. Cell 2001;106(4):489–98.PubMed

80.

Osmani N, Vitale N, Borg JP, Etienne-Manneville S. Scrib controls Cdc42 localization and activity to promote cell polarization during astrocyte migration. Curr Biol. 2006;16(24):2395–405.PubMed

81.

Dow LE, Kauffman JS, Caddy J, Zarbalis K, Peterson AS, Jane SM, et al. The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge. Oncogene 2007;26(16):2272–82.PubMed

82.

Schlessinger K, McManus EJ, Hall A. Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity. J Cell Biol. 2007;178(3):355–61.PubMed

83.

Rodriguez OC, Schaefer AW, Mandato CA, Forscher P, Bement WM, Waterman-Storer CM. Conserved microtubule-actin interactions in cell movement and morphogenesis. Nat Cell Biol. 2003;5(7):599–609.PubMed

84.

Schwartz MA, Shattil SJ. Signaling networks linking integrins and rho family GTPases. Trends Biochem Sci. 2000;25(8):388–91.PubMed

85.

Kiosses WB, Shattil SJ, Pampori N, Schwartz MA. Rac recruits high-affinity integrin alphavbeta3 to lamellipodia in endothelial cell migration. Nat Cell Biol. 2001;3(3):316–20.PubMed

86.

Pegtel DM, Ellenbroek SI, Mertens AE, van der Kammen RA, de Rooij J, Collard JG. The Par-Tiam1 complex controls persistent migration by stabilizing microtubule-dependent front-rear polarity. Curr Biol. 2007;17(19):1623–34.PubMed

87.

Shin K, Wang Q, Margolis B. PATJ regulates directional migration of mammalian epithelial cells. EMBO Rep. 2007;8(2):158–64.PubMed

88.

Nakayama M, Goto TM, Sugimoto M, Nishimura T, Shinagawa T, Ohno S, et al. Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation. Dev Cell. 2008;14(2):205–15.PubMed

89.

Etienne-Manneville S, Hall A. Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity. Nature 2003;421(6924):753–6.PubMed

90.

Jiang W, Betson M, Mulloy R, Foster R, Levay M, Ligeti E, et al. p190A RhoGAP is a glycogen synthase kinase-3-beta substrate required for polarized cell migration. J Biol Chem. 2008;283(30):20978–88.PubMed

91.

Nishimura T, Kaibuchi K. Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3. Dev Cell. 2007;13(1):15–28.PubMed

92.

Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA. 2006;103(35):13180–5.PubMed

93.

Lee EH, Joo CK. Role of transforming growth factor-beta in transdifferentiation and fibrosis of lens epithelial cells. Invest Ophthalmol Vis Sci. 1999;40(9):2025–32.PubMed

94.

Nightingale J, Patel S, Suzuki N, Buxton R, Takagi KI, Suzuki J, et al. Oncostatin M, a cytokine released by activated mononuclear cells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation. J Am Soc Nephrol. 2004;15(1):21–32.PubMed

95.

Oldfield MD, Bach LA, Forbes JM, Nikolic-Paterson D, McRobert A, Thallas V, et al. Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). J Clin Invest. 2001;108(12):1853–63.PubMed

96.

Selman M, Pardo A. Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proc Am Thorac Soc. 2006;3(4):364–72.PubMed

97.

Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol. 2005;166(5):1321–32.PubMed

98.

Boyd NF, Rommens JM, Vogt K, Lee V, Hopper JL, Yaffe MJ, et al. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol. 2005;6(10):798–808.PubMed

99.

Petersen OW, Nielsen HL, Gudjonsson T, Villadsen R, Rank F, Niebuhr E, et al. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol. 2003;162(2):391–402.PubMed

100.

Radisky DC, Kenny PA, Bissell MJ. Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem. 2007;101(4):830–9.PubMed

101.

Ewald AJ, Brenot A, Duong M, Chan BS, Werb Z. Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis. Dev Cell. 2008;14(4):570–81.PubMed

102.

Fata JE, Werb Z, Bissell MJ. Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast Cancer Res. 2004;6(1):1–11.PubMed

103.

Gajewska M, Sobolewska A, Kozlowski M, Motyl T. Role of autophagy in mammary gland development. J Physiol Pharmacol. 2008;59 Suppl 9:237–49.PubMed

104.

Aranda V, Haire T, Nolan ME, Calarco JP, Rosenberg AZ, Fawcett JP, et al. Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nat Cell Biol. 2006;8(11):1235–45.PubMed

105.

Zhan L, Rosenberg A, Bergami KC, Yu M, Xuan Z, Jaffe AB, et al. Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell 2008;135(5):865–78.PubMed

106.

Grunert S, Jechlinger M, Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol. 2003;4(8):657–65.PubMed

107.

Leroy P, Mostov KE. Slug is required for cell survival during partial epithelial-mesenchymal transition of HGF-induced tubulogenesis. Mol Biol Cell. 2007;18(5):1943–52.PubMed

108.

O’Brien LE, Tang K, Kats ES, Schutz-Geschwender A, Lipschutz JH, Mostov KE. ERK and MMPs sequentially regulate distinct stages of epithelial tubule development. Dev Cell. 2004;7(1):21–32.PubMed

109.

Visvader JE, Lindeman GJ. Mammary stem cells and mammopoiesis. Cancer Res. 2006;66(20):9798–801.PubMed

110.

Le Borgne R, Bellaiche Y, Schweisguth F. Drosophila E-cadherin regulates the orientation of asymmetric cell division in the sensory organ lineage. Curr Biol. 2002;12(2):95–104.PubMed

111.

Yamashita YM, Yuan H, Cheng J, Hunt AJ. Polarity in stem cell division: asymmetric stem cell division in tissue homeostasis. Cold Spring Harb Perspect Biol. 2(1):Published online doi:10.1101/cshperspect.a001313.

112.

Gonczy P. Mechanisms of asymmetric cell division: flies and worms pave the way. Nat Rev Mol Cell Biol. 2008;9(5):355–66.PubMed

113.

Zhong W. Timing cell-fate determination during asymmetric cell divisions. Curr Opin Neurobiol. 2008;18(5):472–8.PubMed

114.

McCaffrey LM, Macara IG. The Par3/aPKC interaction is essential for end bud remodeling and progenitor differentiation during mammary gland morphogenesis. Genes Dev. 2009;23(12):1450–60.PubMed

115.

Streuli CH. Integrins and cell-fate determination. J Cell Sci. 2009;122(Pt 2):171–7.PubMed

116.

Visvader JE. Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev. 2009;23(22):2563–77.PubMed

117.

Polyak K. On the birth of breast cancer. Biochim Biophys Acta. 2001;1552(1):1–13.PubMed

118.

van de Vijver MJ. Biological variables and prognosis of DCIS. Breast 2005;14(6):509–19.PubMed

119.

Emery LA, Tripathi A, King C, Kavanah M, Mendez J, Stone MD, et al. Early dysregulation of cell adhesion and extracellular matrix pathways in breast cancer progression. Am J Pathol. 2009;175(3):1292–302.PubMed

120.

Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E, et al. Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene 2003;22(13):2021–33.PubMed

121.

Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS, et al. High-throughput mapping of a dynamic signaling network in mammalian cells. Science 2005;307(5715):1621–5.PubMed

122.

Bose R, Wrana JL. Regulation of Par6 by extracellular signals. Curr Opin Cell Biol. 2006;18(2):206–12.PubMed

123.

Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 2005;307(5715):1603–9.PubMed

124.

Wang HR, Zhang Y, Ozdamar B, Ogunjimi AA, Alexandrova E, Thomsen GH, et al. Regulation of cell polarity and protrusion formation by targeting RhoA for degradation. Science 2003;302(5651):1775–9.PubMed

125.

Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M, et al. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 2007;26(49):6979–88.PubMed

126.

Michel D, Arsanto JP, Massey-Harroche D, Beclin C, Wijnholds J, Le Bivic A. PATJ connects and stabilizes apical and lateral components of tight junctions in human intestinal cells. J Cell Sci. 2005;118(Pt 17):4049–57.PubMed

127.

Roh MH, Liu CJ, Laurinec S, Margolis B. The carboxyl terminus of zona occludens-3 binds and recruits a mammalian homologue of discs lost to tight junctions. J Biol Chem. 2002;277(30):27501–9.PubMed

128.

Massey-Harroche D, Delgrossi MH, Lane-Guermonprez L, Arsanto JP, Borg JP, Billaud M, et al. Evidence for a molecular link between the tuberous sclerosis complex and the Crumbs complex. Hum Mol Genet. 2007;16(5):529–36.PubMed

129.

van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999–2009.PubMed

130.

Creighton CJ. A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors. Oncogene 2007;26(32):4648–55.PubMed

131.

Carraway CA, Carraway KL. Sequestration and segregation of receptor kinases in epithelial cells: implications for ErbB2 oncogenesis. Sci STKE. 2007;2007(381):re3.

132.

Ramsauer VP, Pino V, Farooq A, Carothers Carraway CA, Salas PJ, Carraway KL. Muc4-ErbB2 complex formation and signaling in polarized CACO-2 epithelial cells indicate that Muc4 acts as an unorthodox ligand for ErbB2. Mol Biol Cell. 2006;17(7):2931–41.PubMed

133.

Guo W, Pylayeva Y, Pepe A, Yoshioka T, Muller WJ, Inghirami G, et al. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 2006;126(3):489–502.PubMed

134.

Feigin ME, Muthuswamy SK. Polarity proteins regulate mammalian cell-cell junctions and cancer pathogenesis. Curr Opin Cell Biol. 2009;21(5):694–700.PubMed

135.

Chen X, Macara IG. Par-3 mediates the inhibition of LIM kinase 2 to regulate cofilin phosphorylation and tight junction assembly. J Cell Biol. 2006;172(5):671–8.PubMed

136.

Vos CB, ter Haar NT, Rosenberg C, Peterse JL, Cleton-Jansen AM, Cornelisse CJ, et al. Genetic alterations on chromosome 16 and 17 are important features of ductal carcinoma in situ of the breast and are associated with histologic type. Br J Cancer. 1999;81(8):1410–8.PubMed

137.

Liu E, Thor A, He M, Barcos M, Ljung BM, Benz C. The HER2 (c-erbB-2) oncogene is frequently amplified in in situ carcinomas of the breast. Oncogene 1992;7(5):1027–32.PubMed

138.

Ramachandra S, Machin L, Ashley S, Monaghan P, Gusterson BA. Immunohistochemical distribution of c-erbB-2 in in situ breast carcinoma-a detailed morphological analysis. J Pathol. 1990;161(1):7–14.PubMed

139.

Bartkova J, Barnes DM, Millis RR, Gullick WJ. Immunohistochemical demonstration of c-erbB-2 protein in mammary ductal carcinoma in situ. Hum Pathol. 1990;21(11):1164–7.PubMed

140.

van de Vijver MJ, Peterse JL, Mooi WJ, Wisman P, Lomans J, Dalesio O, et al. Neu-protein overexpression in breast cancer. Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. N Engl J Med. 1988;319(19):1239–45.PubMedCrossRef

141.

Kim M, Datta A, Brakeman P, Yu W, Mostov KE. Polarity proteins PAR6 and aPKC regulate cell death through GSK-3beta in 3D epithelial morphogenesis. J Cell Sci. 2007;120(Pt 14):2309–17.PubMed

142.

Nolan ME, Aranda V, Lee S, Lakshmi B, Basu S, Allred DC, et al. The polarity protein Par6 induces cell proliferation and is overexpressed in breast cancer. Cancer Res. 2008;68(20):8201–9.PubMed

143.

Viloria-Petit AM, David L, Jia JY, Erdemir T, Bane AL, Pinnaduwage D, et al. A role for the TGFbeta-Par6 polarity pathway in breast cancer progression. Proc Natl Acad Sci USA. 2009;106(33):14028–33.PubMed

144.

Xie L, Law BK, Chytil AM, Brown KA, Aakre ME, Moses HL. Activation of the Erk pathway is required for TGF-beta1-induced EMT in vitro. Neoplasia 2004;6(5):603–10.PubMed

145.

Dow LE, Elsum IA, King CL, Kinross KM, Richardson HE, Humbert PO. Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling. Oncogene 2008;27(46):5988–6001.PubMed

146.

Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17(5):548–58.PubMed

147.

Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7(6):415–28.PubMed

148.

Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.PubMed

149.

Sabbah M, Emami S, Redeuilh G, Julien S, Prevost G, Zimber A, et al. Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. Drug Resist Updat. 2008;11(4–5):123–51.PubMed

150.

Attisano L, Wrana JL. Signal transduction by the TGF-beta superfamily. Science 2002;296(5573):1646–7.PubMed

151.

Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425(6958):577–84.PubMed

152.

Kang JS, Liu C, Derynck R. New regulatory mechanisms of TGF-beta receptor function. Trends Cell Biol. 2009;19(8):385–94.PubMed

153.

Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003;113(6):685–700.PubMed

154.

Viloria-Petit AM, Wrana JL. The TGFbeta-Par6 polarity pathway: linking the Par complex to EMT and breast cancer progression. Cell Cycle. 2010;9(4):623–4.

155.

Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, et al. Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol. 2002;156(2):299–313.PubMed

156.

Seton-Rogers SE, Lu Y, Hines LM, Koundinya M, LaBaer J, Muthuswamy SK, et al. Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci USA. 2004;101(5):1257–62.PubMed

157.

Derksen PW, Liu X, Saridin F, van der Gulden H, Zevenhoven J, Evers B, et al. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell. 2006;10(5):437–49.PubMed

158.

Hellman S, Heimann R. The clinical significance of tumor progression: breast cancer as a model. Cancer J. 2000;6 Suppl 2:S131–3.PubMed

159.

Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008;68(10):3645–54.PubMed

160.

Wong AS, Gumbiner BM. Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J Cell Biol. 2003;161(6):1191–203.PubMed

161.

Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2(2):84–9.PubMed

162.

Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2(2):76–83.PubMed

163.

Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell. 2001;7(6):1267–78.PubMed

164.

Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M, et al. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 2005;24(14):2375–85.PubMed

165.

Hajra KM, Chen DY, Fearon ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 2002;62(6):1613–8.PubMed

166.

Sobrado VR, Moreno-Bueno G, Cubillo E, Holt LJ, Nieto MA, Portillo F, et al. The class I bHLH factors E2-2A and E2-2B regulate EMT. J Cell Sci. 2009;122(Pt 7):1014–24.PubMed

167.

Ikenouchi J, Matsuda M, Furuse M, Tsukita S. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci. 2003;116(Pt 10):1959–67.PubMed

168.

Spaderna S, Schmalhofer O, Wahlbuhl M, Dimmler A, Bauer K, Sultan A, et al. The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res. 2008;68(2):537–44.PubMed

169.

Wang Z, Wade P, Mandell KJ, Akyildiz A, Parkos CA, Mrsny RJ, et al. Raf 1 represses expression of the tight junction protein occludin via activation of the zinc-finger transcription factor slug. Oncogene 2007;26(8):1222–30.PubMed

170.

Escriva M, Peiro S, Herranz N, Villagrasa P, Dave N, Montserrat-Sentis B, et al. Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Mol Cell Biol. 2008;28(5):1528–40.PubMed

171.

Moreno-Bueno G, Portillo F, Cano A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 2008;27(55):6958–69.PubMed

172.

Wu Y, Evers BM, Zhou BP. Small C-terminal domain phosphatase enhances snail activity through dephosphorylation. J Biol Chem. 2009;284(1):640–8.PubMed

173.

Wyatt L, Wadham C, Crocker LA, Lardelli M, Khew-Goodall Y. The protein tyrosine phosphatase Pez regulates TGFbeta, epithelial-mesenchymal transition, and organ development. J Cell Biol. 2007;178(7):1223–35.PubMed

174.

Peinado H, Del Carmen Iglesias-de la Cruz M, Olmeda D, Csiszar K, Fong KS, Vega S, et al. A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J. 2005;24(19):3446–58.PubMed

175.

Cano A, Nieto MA. Non-coding RNAs take centre stage in epithelial-to-mesenchymal transition. Trends Cell Biol. 2008;18(8):357–9.PubMed

176.

Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008;9(6):582–9.PubMed

177.

Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593–601.PubMed

178.

Arima Y, Inoue Y, Shibata T, Hayashi H, Nagano O, Saya H, et al. Rb depletion results in deregulation of E-cadherin and induction of cellular phenotypic changes that are characteristic of the epithelial-to-mesenchymal transition. Cancer Res. 2008;68(13):5104–12.PubMed

179.

Bryant DM, Stow JL. The ins and outs of E-cadherin trafficking. Trends Cell Biol. 2004;14(8):427–34.PubMed

180.

Georgiou M, Marinari E, Burden J, Baum B. Cdc42, Par6, and aPKC regulate Arp2/3-mediated endocytosis to control local adherens junction stability. Curr Biol. 2008;18(21):1631–8.PubMed

181.

Harris KP, Tepass U. Cdc42 and Par proteins stabilize dynamic adherens junctions in the Drosophila neuroectoderm through regulation of apical endocytosis. J Cell Biol. 2008;183(6):1129–43.PubMed

182.

Berns EM, Klijn JG, van Putten WL, van Staveren IL, Portengen H, Foekens JA. c-myc amplification is a better prognostic factor than HER2/neu amplification in primary breast cancer. Cancer Res. 1992;52(5):1107–13.PubMed

183.

Akiyama T, Matsuda S, Namba Y, Saito T, Toyoshima K, Yamamoto T. The transforming potential of the c-erbB-2 protein is regulated by its autophosphorylation at the carboxyl-terminal domain. Mol Cell Biol. 1991;11(2):833–42.PubMed

184.

Robanus-Maandag EC, Bosch CA, Kristel PM, Hart AA, Faneyte IF, Nederlof PM, et al. Association of C-MYC amplification with progression from the in situ to the invasive stage in C-MYC-amplified breast carcinomas. J Pathol. 2003;201(1):75–82.PubMed

185.

Varley JM, Swallow JE, Brammar WJ, Whittaker JL, Walker RA. Alterations to either c-erbB-2(neu) or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis. Oncogene 1987;1(4):423–30.PubMed

186.

Navarro C, Nola S, Audebert S, Santoni MJ, Arsanto JP, Ginestier C, et al. Junctional recruitment of mammalian Scribble relies on E-cadherin engagement. Oncogene 2005;24(27):4330–9.PubMed

187.

Reischauer S, Levesque MP, Nusslein-Volhard C, Sonawane M. Lgl2 executes its function as a tumor suppressor by regulating ErbB signaling in the zebrafish epidermis. PLoS Genet. 2009;5(11):e1000720.PubMed

188.

Hoshino M, Yoshimori T, Nakamura S. Small GTPase proteins Rin and Rit Bind to PAR6 GTP-dependently and regulate cell transformation. J Biol Chem. 2005;280(24):22868–74.PubMed

189.

Pece S, Serresi M, Santolini E, Capra M, Hulleman E, Galimberti V, et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol. 2004;167(2):215–21.PubMed

190.

Dotto GP. Notch tumor suppressor function. Oncogene 2008;27(38):5115–23.PubMed

191.

Frise E, Knoblich JA, Younger-Shepherd S, Jan LY, Jan YN. The Drosophila Numb protein inhibits signaling of the Notch receptor during cell-cell interaction in sensory organ lineage. Proc Natl Acad Sci USA. 1996;93(21):11925–32.PubMed

192.

Colaluca IN, Tosoni D, Nuciforo P, Senic-Matuglia F, Galimberti V, Viale G, et al. NUMB controls p53 tumour suppressor activity. Nature 2008;451(7174):76–80.PubMed

193.

Rennstam K, McMichael N, Berglund P, Honeth G, Hegardt C, Ryden L, et al. Numb protein expression correlates with a basal-like phenotype and cancer stem cell markers in primary breast cancer. Breast Cancer Res Treat. 2009:Publisher online doi:10.1007/s10549-009-0568-x.

194.

Tarin D, Thompson EW, Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res. 2005;65(14):5996–6000. discussion 6000-1.PubMed

195.

Zeisberg M, Shah AA, Kalluri R. Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J Biol Chem. 2005;280(9):8094–100.PubMed

196.

Dressler GR. The cellular basis of kidney development. Annu Rev Cell Dev Biol. 2006;22:509–29.PubMed

197.

Olmeda D, Jorda M, Peinado H, Fabra A, Cano A. Snail silencing effectively suppresses tumour growth and invasiveness. Oncogene 2007;26(13):1862–74.PubMed

198.

Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, Williams ED. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res. 2006;66(23):11271–8.PubMed

199.

Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.PubMed

200.

Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414(6859):105–11.PubMed

201.

Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100(7):3983–8.PubMed

202.

Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007;131(6):1109–23.PubMed

203.

Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672–9.PubMed

204.

Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 2009;138(4):645–59.PubMed

205.

Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008;133(4):704–15.PubMed

206.

Hollier BG, Evans K, Mani SA. The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia. 2009;14(1):29–43.PubMed

207.

Smalley MJ, Dale TC. Wnt signaling and mammary tumorigenesis. J Mammary Gland Biol Neoplasia. 2001;6(1):37–52.PubMed

208.

Howe LR, Brown AM. Wnt signaling and breast cancer. Cancer Biol Ther. 2004;3(1):36–41.PubMed

209.

Brennan KR, Brown AM. Wnt proteins in mammary development and cancer. J Mammary Gland Biol Neoplasia. 2004;9(2):119–31.PubMed

210.

Li Y, Hively WP, Varmus HE. Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer. Oncogene 2000;19(8):1002–9.PubMed

211.

Michaelson JS, Leder P. beta-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland. Oncogene 2001;20(37):5093–9.PubMed

212.

Imbert A, Eelkema R, Jordan S, Feiner H, Cowin P. Delta N89 beta-catenin induces precocious development, differentiation, and neoplasia in mammary gland. J Cell Biol. 2001;153(3):555–68.PubMed

213.

Hatsell S, Rowlands T, Hiremath M, Cowin P. Beta-catenin and Tcfs in mammary development and cancer. J Mammary Gland Biol Neoplasia. 2003;8(2):145–58.PubMed

214.

Eger A, Stockinger A, Park J, Langkopf E, Mikula M, Gotzmann J, et al. beta-Catenin and TGFbeta signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition. Oncogene 2004;23(15):2672–80.PubMed

215.

Liu BY, McDermott SP, Khwaja SS, Alexander CM. The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. Proc Natl Acad Sci USA. 2004;101(12):4158–63.PubMed

216.

Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci USA. 2003;100(26):15853–8.PubMed

217.

Katoh Y, Katoh M. Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). Int J Mol Med. 2008;22(3):271–5.PubMed

218.

Grego-Bessa J, Diez J, Timmerman L, de la Pompa JL. Notch and epithelial-mesenchyme transition in development and tumor progression: another turn of the screw. Cell Cycle. 2004;3(6):718–21.PubMed

219.

Weaver VM, Petersen OW, Wang F, Larabell CA, Briand P, Damsky C, et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol. 1997;137(1):231–45.PubMed

220.

Zutter MM, Santoro SA, Staatz WD, Tsung YL. Re-expression of the alpha 2 beta 1 integrin abrogates the malignant phenotype of breast carcinoma cells. Proc Natl Acad Sci USA. 1995;92(16):7411–5.PubMed

221.

Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004;117(7):927–39.PubMed

222.

Come C, Magnino F, Bibeau F, De Santa Barbara P, Becker KF, Theillet C, et al. Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res. 2006;12(18):5395–402.PubMed

223.

Trimboli AJ, Fukino K, de Bruin A, Wei G, Shen L, Tanner SM, et al. Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res. 2008;68(3):937–45.PubMed

224.

Latta EK, Tjan S, Parkes RK, O’Malley FP. The role of HER2/neu overexpression/amplification in the progression of ductal carcinoma in situ to invasive carcinoma of the breast. Mod Pathol. 2002;15(12):1318–25.PubMed

225.

Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 2003;100(14):8418–23.PubMed

226.

Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869–74.PubMed

227.

Sarrio D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 2008;68(4):989–97.PubMed

228.

Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature 2000;406(6797):747–52.PubMed

229.

Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS, et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 2009;69(10):4116–24.PubMed

230.

Fulford LG, Easton DF, Reis-Filho JS, Sofronis A, Gillett CE, Lakhani SR, et al. Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast. Histopathology 2006;49(1):22–34.PubMed

231.

Carter MR, Hornick JL, Lester S, Fletcher CD. Spindle cell (sarcomatoid) carcinoma of the breast: a clinicopathologic and immunohistochemical analysis of 29 cases. Am J Surg Pathol. 2006;30(3):300–9.PubMed

232.

Rodriguez-Pinilla SM, Sarrio D, Honrado E, Hardisson D, Calero F, Benitez J, et al. Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res. 2006;12(5):1533–9.PubMed

233.

Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10(16):5367–74.PubMed

234.

Li QQ, Xu JD, Wang WJ, Cao XX, Chen Q, Tang F, et al. Twist1-mediated adriamycin-induced epithelial-mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells. Clin Cancer Res. 2009;15(8):2657–65.PubMed

235.

Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene 2005;24(50):7443–54.PubMed

236.

Thiery JP, Huang R. Linking epithelial-mesenchymal transition to the well-known polarity protein Par6. Dev Cell. 2005;8(4):456–8.PubMed

237.

Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7(2):131–42.PubMed

238.

Wang X, Nie J, Zhou Q, Liu W, Zhu F, Chen W, et al. Downregulation of Par-3 expression and disruption of Par complex integrity by TGF-beta during the process of epithelial to mesenchymal transition in rat proximal epithelial cells. Biochim Biophys Acta. 2008;1782(1):51–9.PubMed

Title: Cell Polarity in Motion: Redefining Mammary Tissue Organization Through EMT and Cell Polarity Transitions
Authors: Nathan J. Godde
Ryan C. Galea
Imogen A. Elsum
Patrick O. Humbert
Publication date: 01-06-2010
Publisher: Springer US
Published in: Journal of Mammary Gland Biology and Neoplasia / Issue 2/2010
Print ISSN: 1083-3021
Electronic ISSN: 1573-7039
DOI: https://doi.org/10.1007/s10911-010-9180-2

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