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Scribble Modulates the MAPK/Fra1 Pathway to Disrupt Luminal and Ductal Integrity and Suppress Tumour Formation in the Mammary Gland


Polarity allows the specialization of cell function and is required to coordinate cell movements, differentiation, proliferation and apoptosis to build and maintain complex tissues such as the mammary gland. Disruption of polarity is a diagnostic criterion of cancer, but exactly how deregulation of core polarity genes contribute to cancer and at which stage polarity loss promotes breast cancer development in vivo is still poorly understood. To address this directly, we deleted the core polarity gene Scrib specifically in the mouse mammary gland. Scrib loss resulted in loss of tissue architecture and duct hyperplasia in mature but not pubescent mice. Onset of hyperplasia was associated with defective spindle orientations, a failure to apoptose and was sustained by high cell turnover and Ras/Erk/Fra1 MAPK pathway activation. Scrib deficiency activated progenitors and resulted in the excess growth of atypical luminal cells and the development of ductal and alveolar hyperplasia. Overall these mice exhibited an increased incidence, onset and grade of mammary tumours. These studies provide a definitive demonstration of the critical role played by core polarity genes in maintaining mammary epithelial integrity in vivo. This mouse model is a valuable tool for understanding the role of polarity in mammary development and the most initial stages of breast cancer.


Vyšlo v časopise: Scribble Modulates the MAPK/Fra1 Pathway to Disrupt Luminal and Ductal Integrity and Suppress Tumour Formation in the Mammary Gland. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004323
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004323

Souhrn

Polarity allows the specialization of cell function and is required to coordinate cell movements, differentiation, proliferation and apoptosis to build and maintain complex tissues such as the mammary gland. Disruption of polarity is a diagnostic criterion of cancer, but exactly how deregulation of core polarity genes contribute to cancer and at which stage polarity loss promotes breast cancer development in vivo is still poorly understood. To address this directly, we deleted the core polarity gene Scrib specifically in the mouse mammary gland. Scrib loss resulted in loss of tissue architecture and duct hyperplasia in mature but not pubescent mice. Onset of hyperplasia was associated with defective spindle orientations, a failure to apoptose and was sustained by high cell turnover and Ras/Erk/Fra1 MAPK pathway activation. Scrib deficiency activated progenitors and resulted in the excess growth of atypical luminal cells and the development of ductal and alveolar hyperplasia. Overall these mice exhibited an increased incidence, onset and grade of mammary tumours. These studies provide a definitive demonstration of the critical role played by core polarity genes in maintaining mammary epithelial integrity in vivo. This mouse model is a valuable tool for understanding the role of polarity in mammary development and the most initial stages of breast cancer.


Zdroje

1. BryantDM, MostovKE (2008) From cells to organs: building polarized tissue. Nat Rev Mol Cell Biol 9: 887–901.

2. DowLE, HumbertPO (2007) Polarity regulators and the control of epithelial architecture, cell migration, and tumorigenesis. Int Rev Cytol 262: 253–302.

3. GoddeNJ, GaleaRC, ElsumIA, HumbertPO (2010) Cell polarity in motion: redefining mammary tissue organization through EMT and cell polarity transitions. J Mammary Gland Biol Neoplasia 15: 149–168.

4. HumbertPO, GrzeschikNA, BrumbyAM, GaleaR, ElsumI, et al. (2008) Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module. Oncogene 27: 6888–6907.

5. SunY, AigaM, YoshidaE, HumbertPO, BamjiSX (2009) Scribble interacts with beta-catenin to localize synaptic vesicles to synapses. Mol Biol Cell 20: 3390–3400.

6. MetaisJY, NavarroC, SantoniMJ, AudebertS, BorgJP (2005) hScrib interacts with ZO-2 at the cell-cell junctions of epithelial cells. FEBS Lett 579: 3725–3730.

7. TakizawaS, NagasakaK, NakagawaS, YanoT, NakagawaK, et al. (2006) Human scribble, a novel tumor suppressor identified as a target of high-risk HPV E6 for ubiquitin-mediated degradation, interacts with adenomatous polyposis coli. Genes Cells 11: 453–464.

8. NagasakaK, PimD, MassimiP, ThomasM, TomaicV, et al. (2010) The cell polarity regulator hScrib controls ERK activation through a KIM site-dependent interaction. Oncogene 29: 5311–5321.

9. KallayLM, McNickleA, BrennwaldPJ, HubbardAL, BraitermanLT (2006) Scribble associates with two polarity proteins, Lgl2 and Vangl2, via distinct molecular domains. J Cell Biochem 99: 647–664.

10. AudebertS, NavarroC, NourryC, Chasserot-GolazS, LecineP, et al. (2004) Mammalian Scribble forms a tight complex with the betaPIX exchange factor. Curr Biol 14: 987–995.

11. VisvaderJE (2009) Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev 23: 2563–2577.

12. EwaldAJ, BrenotA, DuongM, ChanBS, WerbZ (2008) Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis. Dev Cell 14: 570–581.

13. EwaldAJ, HuebnerRJ, PalsdottirH, LeeJK, PerezMJ, et al. (2012) Mammary collective cell migration involves transient loss of epithelial features and individual cell migration within the epithelium. J Cell Sci

14. JanuschkeJ, GonzalezC (2008) Drosophila asymmetric division, polarity and cancer. Oncogene 27: 6994–7002.

15. MorinX, BellaicheY (2011) Mitotic spindle orientation in asymmetric and symmetric cell divisions during animal development. Dev Cell 21: 102–119.

16. CicaleseA, BonizziG, PasiCE, FarettaM, RonzoniS, et al. (2009) The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138: 1083–1095.

17. McCaffreyLM, MacaraIG (2009) The Par3/aPKC interaction is essential for end bud remodeling and progenitor differentiation during mammary gland morphogenesis. Genes Dev 23: 1450–1460.

18. BissellMJ, RadiskyD (2001) Putting tumours in context. Nat Rev Cancer 1: 46–54.

19. BilderD, LiM, PerrimonN (2000) Cooperative Regulation of Cell Polarity and Growth by Drosophila Tumor Suppressors. Science 289: 113–116.

20. GardiolD, ZacchiA, PetreraF, StantaG, BanksL (2006) Human discs large and scrib are localized at the same regions in colon mucosa and changes in their expression patterns are correlated with loss of tissue architecture during malignant progression. Int J Cancer 119: 1285–1290.

21. KameiY, KitoK, TakeuchiT, ImaiY, MuraseR, et al. (2007) Human scribble accumulates in colorectal neoplasia in association with an altered distribution of beta-catenin. Hum Pathol 38: 1273–1281.

22. LisovskyM, DresserK, BakerS, FisherA, WodaB, et al. (2009) Cell polarity protein Lgl2 is lost or aberrantly localized in gastric dysplasia and adenocarcinoma: an immunohistochemical study. Mod Pathol 22: 977–984.

23. LisovskyM, OgawaF, DresserK, WodaB, LauwersGY (2010) Loss of cell polarity protein Lgl2 in foveolar-type gastric dysplasia: correlation with expression of the apical marker aPKC-zeta. Virchows Arch 457: 635–642.

24. OuyangZ, ZhanW, DanL (2010) hScrib, a human homolog of Drosophila neoplastic tumor suppressor, is involved in the progress of endometrial cancer. Oncol Res 18: 593–599.

25. PearsonHB, Perez-ManceraPA, DowLE, RyanA, TennstedtP, et al. (2011) SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia. J Clin Invest 121: 4257–67.

26. FujaTJ, LinF, OsannKE, BryantPJ (2004) Somatic mutations and altered expression of the candidate tumor suppressors CSNK1 epsilon, DLG1, and EDD/hHYD in mammary ductal carcinoma. Cancer Res 64: 942–951.

27. MetodievaG, Nogueira-de-SouzaNC, GreenwoodC, Al-JanabiK, LengL, et al. (2013) CD74-dependent Deregulation of the Tumor Suppressor Scribble in Human Epithelial and Breast Cancer Cells. Neoplasia 15: 660–668.

28. NavarroC, NolaS, AudebertS, SantoniMJ, ArsantoJP, et al. (2005) Junctional recruitment of mammalian Scribble relies on E-cadherin engagement. Oncogene 24: 4330–4339.

29. ZhanL, RosenbergA, BergamiKC, YuM, XuanZ, et al. (2008) Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell 135: 865–878.

30. NakagawaS, YanoT, NakagawaK, TakizawaS, SuzukiY, et al. (2004) Analysis of the expression and localisation of a LAP protein, human scribble, in the normal and neoplastic epithelium of uterine cervix. Br J Cancer 90: 194–199.

31. DowLE, ElsumIA, KingCL, KinrossKM, RichardsonHE, et al. (2008) Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling. Oncogene 27: 5988–6001.

32. YatesLL, SchnatwinkelC, HazelwoodL, ChessumL, PaudyalA, et al. (2013) Scribble is required for normal epithelial cell-cell contacts and lumen morphogenesis in the mammalian lung. Dev Biol 373: 267–280.

33. WagnerKU, WallRJ, St-OngeL, GrussP, Wynshaw-BorisA, et al. (1997) Cre-mediated gene deletion in the mammary gland. Nucleic Acids Res 25: 4323–4330.

34. PalB, BourasT, ShiW, VaillantF, SheridanJM, et al. (2013) Global changes in the mammary epigenome are induced by hormonal cues and coordinated by Ezh2. Cell Rep 3: 411–426.

35. WagnerKU, McAllisterK, WardT, DavisB, WisemanR, et al. (2001) Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Res 10: 545–553.

36. PitelkaDR, HamamotoST, DuafalaJG, NemanicMK (2009) Cell contacts in the mouse mammary gland: i. Normal gland in postnatal development and the secretory cycle. 1973. J Mammary Gland Biol Neoplasia 14: 295–316.

37. ElsumIA, MartinC, HumbertPO (2013) Scribble regulates an EMT-polarity pathway through modulation of MAPK-ERK signaling to mediate junction formation. J Cell Sci 126: 3990–9.

38. IvanovAI, YoungC, Den BesteK, CapaldoCT, HumbertPO, et al. (2010) Tumor suppressor scribble regulates assembly of tight junctions in the intestinal epithelium. Am J Pathol 176: 134–145.

39. QinY, CapaldoC, GumbinerBM, MacaraIG (2005) The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J Cell Biol 171: 1061–1071.

40. DowLE, KauffmanJS, CaddyJ, ZarbalisK, PetersonAS, et al. (2007) The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge. Oncogene 26: 2272–2282.

41. HumphreysRC, KrajewskaM, KrnacikS, JaegerR, WeiherH, et al. (1996) Apoptosis in the terminal endbud of the murine mammary gland: a mechanism of ductal morphogenesis. Development 122: 4013–4022.

42. MailleuxAA, OverholtzerM, BruggeJS (2008) Lumen formation during mammary epithelial morphogenesis: insights from in vitro and in vivo models. Cell Cycle 7: 57–62.

43. ReginatoMJ, MuthuswamySK (2006) Illuminating the center: mechanisms regulating lumen formation and maintenance in mammary morphogenesis. J Mammary Gland Biol Neoplasia 11: 205–211.

44. FrankSR, BellJH, FrodinM, HansenSH (2012) A betaPIX-PAK2 Complex Confers Protection against Scrib-Dependent and Cadherin-Mediated Apoptosis. Curr Biol 22: 1747–54.

45. LiuH, GolebiewskiL, DowEC, KrugRM, JavierRT, et al. (2010) The ESEV PDZ-binding motif of the avian influenza A virus NS1 protein protects infected cells from apoptosis by directly targeting Scribble. J Virol 84: 11164–11174.

46. AlbertsonR, DoeCQ (2003) Dlg, Scrib and Lgl regulate neuroblast cell size and mitotic spindle asymmetry. Nat Cell Biol 5: 166–170.

47. den ElzenN, ButteryCV, MaddugodaMP, RenG, YapAS (2009) Cadherin adhesion receptors orient the mitotic spindle during symmetric cell division in mammalian epithelia. Mol Biol Cell 20: 3740–3750.

48. DurganJ, KajiN, JinD, HallA (2011) Par6B and atypical PKC (aPKC) regulate mitotic spindle orientation during epithelial morphogenesis. J Biol Chem 286: 12461–74.

49. ToyoshimaF, MatsumuraS, MorimotoH, MitsushimaM, NishidaE (2007) PtdIns(3,4,5)P3 regulates spindle orientation in adherent cells. Dev Cell 13: 796–811.

50. MitsushimaM, ToyoshimaF, NishidaE (2009) Dual role of Cdc42 in spindle orientation control of adherent cells. Mol Cell Biol 29: 2816–2827.

51. OsmaniN, VitaleN, BorgJP, Etienne-MannevilleS (2006) Scrib controls Cdc42 localization and activity to promote cell polarization during astrocyte migration. Curr Biol 16: 2395–2405.

52. ShackletonM, VaillantF, SimpsonKJ, StinglJ, SmythGK, et al. (2006) Generation of a functional mammary gland from a single stem cell. Nature 439: 84–88.

53. BourasT, PalB, VaillantF, HarburgG, Asselin-LabatML, et al. (2008) Notch signaling regulates mammary stem cell function and luminal cell-fate commitment. Cell Stem Cell 3: 429–441.

54. Asselin-LabatML, SutherlandKD, BarkerH, ThomasR, ShackletonM, et al. (2007) Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol 9: 201–209.

55. LimE, VaillantF, WuD, ForrestNC, PalB, et al. (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15: 907–913.

56. OakesSR, NaylorMJ, Asselin-LabatML, BlazekKD, Gardiner-GardenM, et al. (2008) The Ets transcription factor Elf5 specifies mammary alveolar cell fate. Genes Dev 22: 581–586.

57. ElsumIA, YatesLL, PearsonHB, PhesseTJ, LongF, et al. (2013) Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo. Oncogene doi: 10.1038/onc.2013.498

58. WhyteJ, BerginO, BianchiA, McNallyS, MartinF (2009) Key signalling nodes in mammary gland development and cancer. Mitogen-activated protein kinase signalling in experimental models of breast cancer progression and in mammary gland development. Breast Cancer Res 11: 209.

59. YoungLC, HartigN, Munoz-AlegreM, Oses-PrietoJA, DurduS, et al. (2013) An MRAS, SHOC2, and SCRIB Complex Coordinates ERK Pathway Activation with Polarity and Tumorigenic Growth. Mol Cell 52: 679–692.

60. LuoYP, ZhouH, KruegerJ, KaplanC, LiaoD, et al. (2010) The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression. Oncogene 29: 662–673.

61. XuKP, DingY, LingJ, DongZ, YuFS (2004) Wound-induced HB-EGF ectodomain shedding and EGFR activation in corneal epithelial cells. Invest Ophthalmol Vis Sci 45: 813–820.

62. LiX, YangH, LiuJ, SchmidtMD, GaoT (2011) Scribble-mediated membrane targeting of PHLPP1 is required for its negative regulation of Akt. EMBO Rep 12: 818–824.

63. MedinaD (2000) The preneoplastic phenotype in murine mammary tumorigenesis. J Mammary Gland Biol Neoplasia 5: 393–407.

64. MiermontAM, ParrishAR, FurthPA (2010) Role of ERalpha in the differential response of Stat5a loss in susceptibility to mammary preneoplasia and DMBA-induced carcinogenesis. Carcinogenesis 31: 1124–1131.

65. RadaelliE, ArnoldA, PapanikolaouA, Garcia-FernandezRA, MattielloS, et al. (2009) Mammary tumor phenotypes in wild-type aging female FVB/N mice with pituitary prolactinomas. Vet Pathol 46: 736–745.

66. CardiffRD, AnverMR, GustersonBA, HennighausenL, JensenRA, et al. (2000) The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting. Oncogene 19: 968–988.

67. MailleuxAA, OverholtzerM, SchmelzleT, BouilletP, StrasserA, et al. (2007) BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanisms. Dev Cell 12: 221–234.

68. ReginatoMJ, MillsKR, BeckerEB, LynchDK, BonniA, et al. (2005) Bim regulation of lumen formation in cultured mammary epithelial acini is targeted by oncogenes. Mol Cell Biol 25: 4591–4601.

69. JechlingerM, PodsypaninaK, VarmusH (2009) Regulation of transgenes in three-dimensional cultures of primary mouse mammary cells demonstrates oncogene dependence and identifies cells that survive deinduction. Genes Dev 23: 1677–1688.

70. PeaseJC, TirnauerJS (2011) Mitotic spindle misorientation in cancer - out of alignment and into the fire. J Cell Sci 124: 1007–1016.

71. TaddeiI, DeugnierMA, FaraldoMM, PetitV, BouvardD, et al. (2008) Beta1 integrin deletion from the basal compartment of the mammary epithelium affects stem cells. Nat Cell Biol 10: 716–722.

72. TangN, MarshallWF, McMahonM, MetzgerRJ, MartinGR (2011) Control of mitotic spindle angle by the RAS-regulated ERK1/2 pathway determines lung tube shape. Science 333: 342–345.

73. KashimataM, SayeedS, KaA, Onetti-MudaA, SakagamiH, et al. (2000) The ERK-1/2 signaling pathway is involved in the stimulation of branching morphogenesis of fetal mouse submandibular glands by EGF. Dev Biol 220: 183–196.

74. FisherCE, MichaelL, BarnettMW, DaviesJA (2001) Erk MAP kinase regulates branching morphogenesis in the developing mouse kidney. Development 128: 4329–4338.

75. BalmannoK, CookSJ (1999) Sustained MAP kinase activation is required for the expression of cyclin D1, p21Cip1 and a subset of AP-1 proteins in CCL39 cells. Oncogene 18: 3085–3097.

76. ChalmersCJ, GilleyR, MarchHN, BalmannoK, CookSJ (2007) The duration of ERK1/2 activity determines the activation of c-Fos and Fra-1 and the composition and quantitative transcriptional output of AP-1. Cell Signal 19: 695–704.

77. FataJE, MoriH, EwaldAJ, ZhangH, YaoE, et al. (2007) The MAPK(ERK-1,2) pathway integrates distinct and antagonistic signals from TGFalpha and FGF7 in morphogenesis of mouse mammary epithelium. Dev Biol 306: 193–207.

78. BaldysA, GoozM, MorinelliTA, LeeMH, RaymondJRJr, et al. (2009) Essential role of c-Cbl in amphiregulin-induced recycling and signaling of the endogenous epidermal growth factor receptor. Biochemistry 48: 1462–1473.

79. PasicL, Eisinger-MathasonTS, VelayudhanBT, MoskalukCA, BreninDR, et al. (2011) Sustained activation of the HER1-ERK1/2-RSK signaling pathway controls myoepithelial cell fate in human mammary tissue. Genes Dev 25: 1641–1653.

80. EcclesSA (2011) The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology. Int J Dev Biol 55: 685–696.

81. PetersenOW, Ronnov-JessenL, HowlettAR, BissellMJ (1992) Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc Natl Acad Sci U S A 89: 9064–9068.

82. WangF, HansenRK, RadiskyD, YonedaT, Barcellos-HoffMH, et al. (2002) Phenotypic reversion or death of cancer cells by altering signaling pathways in three-dimensional contexts. J Natl Cancer Inst 94: 1494–1503.

83. BeliveauA, MottJD, LoA, ChenEI, KollerAA, et al. (2010) Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo. Genes Dev 24: 2800–2811.

84. MuthuswamySK, LiD, LelievreS, BissellMJ, BruggeJS (2001) ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini. Nat Cell Biol 3: 785–792.

85. WarrenSL, HandelLM, NelsonWJ (1988) Elevated expression of pp60c-src alters a selective morphogenetic property of epithelial cells in vitro without a mitogenic effect. Mol Cell Biol 8: 632–646.

86. AndrechekER, WhiteD, MullerWJ (2005) Targeted disruption of ErbB2/Neu in the mammary epithelium results in impaired ductal outgrowth. Oncogene 24: 932–937.

87. GuyCT, CardiffRD, MullerWJ (1996) Activated neu induces rapid tumor progression. J Biol Chem 271: 7673–7678.

88. EspinaV, LiottaLA (2010) What is the malignant nature of human ductal carcinoma in situ? Nat Rev Cancer 11: 68–75.

89. van de VijverMJ (2005) Biological variables and prognosis of DCIS. Breast 14: 509–519.

90. LiuE, ThorA, HeM, BarcosM, LjungBM, et al. (1992) The HER2 (c-erbB-2) oncogene is frequently amplified in in situ carcinomas of the breast. Oncogene 7: 1027–1032.

91. MittalS, SubramanyamD, DeyD, KumarRV, RangarajanA (2009) Cooperation of Notch and Ras/MAPK signaling pathways in human breast carcinogenesis. Mol Cancer 8: 128.

92. van de VijverMJ, PeterseJL, MooiWJ, WismanP, LomansJ, et al. (1988) 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 319: 1239–1245.

93. VosCB, ter HaarNT, RosenbergC, PeterseJL, Cleton-JansenAM, et al. (1999) 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 81: 1410–1418.

94. SongY, SongS, ZhangD, ZhangY, ChenL, et al. (2006) An association of a simultaneous nuclear and cytoplasmic localization of Fra-1 with breast malignancy. BMC Cancer 6: 298.

95. ChiappettaG, FerraroA, BottiG, MonacoM, PasquinelliR, et al. (2007) FRA-1 protein overexpression is a feature of hyperplastic and neoplastic breast disorders. BMC Cancer 7: 17.

96. ZajchowskiDA, BartholdiMF, GongY, WebsterL, LiuHL, et al. (2001) Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res 61: 5168–5178.

97. LogulloAF, StiepcichMM, OsorioCA, NonogakiS, PasiniFS, et al. (2011) Role of Fos-related antigen 1 in the progression and prognosis of ductal breast carcinoma. Histopathology 58: 617–625.

98. PhilipsA, ChalbosD, RochefortH (1993) Estradiol increases and anti-estrogens antagonize the growth factor-induced activator protein-1 activity in MCF7 breast cancer cells without affecting c-fos and c-jun synthesis. J Biol Chem 268: 14103–14108.

99. BelguiseK, KersualN, GaltierF, ChalbosD (2005) FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells. Oncogene 24: 1434–1444.

100. LambeM, HsiehCC, ChanHW, EkbomA, TrichopoulosD, et al. (1996) Parity, age at first and last birth, and risk of breast cancer: a population-based study in Sweden. Breast Cancer Res Treat 38: 305–311.

101. RussoIH, RussoJ (2011) Pregnancy-induced changes in breast cancer risk. J Mammary Gland Biol Neoplasia 16: 221–233.

102. DowLE, BrumbyAM, MuratoreR, CoombeML, SedeliesKA, et al. (2003) hScrib is a functional homologue of the Drosophila tumour suppressor Scribble. Oncogene 22: 9225–9230.

103. LivakKJ, SchmittgenTD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25: 402–408.

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