The Gene Desert Mammary Carcinoma Susceptibility Locus Regulates Modifying Mammary Epithelial Cell Differentiation and Proliferation

English version České info

Genome-wide association studies have revealed that many low-penetrance breast cancer susceptibility loci are located in non-protein coding genomic regions; however, few have been characterized. In a comparative genetics approach to model such loci in a rat breast cancer model, we previously identified the mammary carcinoma susceptibility locus Mcs1a. We now localize Mcs1a to a critical interval (277 Kb) within a gene desert. Mcs1a reduces mammary carcinoma multiplicity by 50% and acts in a mammary cell-autonomous manner. We developed a megadeletion mouse model, which lacks 535 Kb of sequence containing the Mcs1a ortholog. Global gene expression analysis by RNA-seq revealed that in the mouse mammary gland, the orphan nuclear receptor gene Nr2f1/Coup-tf1 is regulated by Mcs1a. In resistant Mcs1a congenic rats, as compared with susceptible congenic control rats, we found Nr2f1 transcript levels to be elevated in mammary gland, epithelial cells, and carcinoma samples. Chromatin looping over ∼820 Kb of sequence from the Nr2f1 promoter to a strongly conserved element within the Mcs1a critical interval was identified. This element contains a 14 bp indel polymorphism that affects a human-rat-mouse conserved COUP-TF binding motif and is a functional Mcs1a candidate. In both the rat and mouse models, higher Nr2f1 transcript levels are associated with higher abundance of luminal mammary epithelial cells. In both the mouse mammary gland and a human breast cancer global gene expression data set, we found Nr2f1 transcript levels to be strongly anti-correlated to a gene cluster enriched in cell cycle-related genes. We queried 12 large publicly available human breast cancer gene expression studies and found that the median NR2F1 transcript level is consistently lower in ‘triple-negative’ (ER-PR-HER2-) breast cancers as compared with ‘receptor-positive’ breast cancers. Our data suggest that the non-protein coding locus Mcs1a regulates Nr2f1, which is a candidate modifier of differentiation, proliferation, and mammary cancer risk.

Vyšlo v časopise: The Gene Desert Mammary Carcinoma Susceptibility Locus Regulates Modifying Mammary Epithelial Cell Differentiation and Proliferation. PLoS Genet 9(6): e32767. doi:10.1371/journal.pgen.1003549
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003549

Souhrn

Zdroje

1. AntoniouAC, EastonDF (2006) Models of genetic susceptibility to breast cancer. Oncogene 25: 5898–5905.

2. MikiY, SwensenJ, Shattuck-EidensD, FutrealPA, HarshmanK, et al. (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66–71.

3. WoosterR, BignellG, LancasterJ, SwiftS, SealS, et al. (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378: 789–792.

4. AhmedS, ThomasG, GhoussainiM, HealeyCS, HumphreysMK, et al. (2009) Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41: 585–590.

5. EastonDF, PooleyKA, DunningAM, PharoahPD, ThompsonD, et al. (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447: 1087–1093.

6. FletcherO, JohnsonN, GibsonL, CouplandB, FraserA, et al. (2008) Association of genetic variants at 8q24 with breast cancer risk. Cancer Epidemiol Biomarkers Prev 17: 702–705.

7. FletcherO, JohnsonN, OrrN, HoskingFJ, GibsonLJ, et al. (2011) Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study. J Natl Cancer Inst 103: 425–435.

8. GhoussainiM, FletcherO, MichailidouK, TurnbullC, SchmidtMK, et al. (2012) Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet 44: 312–318.

9. HunterDJ, KraftP, JacobsKB, CoxDG, YeagerM, et al. (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39: 870–874.

10. StaceySN, ManolescuA, SulemP, RafnarT, GudmundssonJ, et al. (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39: 865–869.

11. StaceySN, ManolescuA, SulemP, ThorlaciusS, GudjonssonSA, et al. (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40: 703–706.

12. ThomasG, JacobsKB, KraftP, YeagerM, WacholderS, et al. (2009) A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41: 579–584.

13. TurnbullC, AhmedS, MorrisonJ, PernetD, RenwickA, et al. (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42: 504–507.

14. ZhengW, LongJ, GaoYT, LiC, ZhengY, et al. (2009) Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41: 324–328.

15. WacholderS, HartgeP, PrenticeR, Garcia-ClosasM, FeigelsonHS, et al. (2010) Performance of common genetic variants in breast-cancer risk models. N Engl J Med 362: 986–993.

16. van ZitterenM, van der NetJB, KunduS, FreedmanAN, van DuijnCM, et al. (2011) Genome-based prediction of breast cancer risk in the general population: a modeling study based on meta-analyses of genetic associations. Cancer Epidemiol Biomarkers Prev 20: 9–22.

17. MeyerKB, MaiaAT, O'ReillyM, TeschendorffAE, ChinSF, et al. (2008) Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLoS Biol 6: e108.

18. SunC, OlopadeOI, Di RienzoA (2010) rs2981582 is associated with FGFR2 expression in normal breast. Cancer Genet Cytogenet 197: 193–194.

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

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

21. StinglJ, EirewP, RicketsonI, ShackletonM, VaillantF, et al. (2006) Purification and unique properties of mammary epithelial stem cells. Nature 439: 993–997.

22. 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.

23. ReganJL, KendrickH, MagnayFA, VafaizadehV, GronerB, et al. (2012) c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer. Oncogene 31: 869–883.

24. ShehataM, TeschendorffA, SharpG, NovcicN, RussellA, et al. (2012) Phenotypic and functional characterization of the luminal cell hierarchy of the mammary gland. Breast Cancer Res 14: R134.

25. SharmaD, SmitsBM, EichelbergMR, MeilahnAL, MuelblMJ, et al. (2011) Quantification of epithelial cell differentiation in mammary glands and carcinomas from DMBA- and MNU-exposed rats. PLoS One 6: e26145.

26. KimND, CliftonKH (1993) Characterization of rat mammary epithelial cell subpopulations by peanut lectin and anti-Thy-1.1 antibody and study of flow-sorted cells in vivo. Exp Cell Res 207: 74–85.

27. RudlandPS (1992) Use of peanut lectin and rat mammary stem cell lines to identify a cellular differentiation pathway for the alveolar cell in the rat mammary gland. J Cell Physiol 153: 157–168.

28. 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.

29. BaiF, SmithMD, ChanHL, PeiXH (2012) Germline mutation of Brca1 alters the fate of mammary luminal cells and causes luminal-to-basal mammary tumor transformation. Oncogene [Epub ahead of print] doi: 10.1038/onc.2012.293

30. DrinkwaterNR, GouldMN (2012) The Long Path from QTL to Gene. PLoS Genet 8: e1002975.

31. HsuLC, KennanWS, ShepelLA, JacobHJ, SzpirerC, et al. (1994) Genetic identification of Mcs-1, a rat mammary carcinoma suppressor gene. Cancer Res 54: 2765–2770.

32. ShepelLA, LanH, HaagJD, BrasicGM, GheenME, et al. (1998) Genetic identification of multiple loci that control breast cancer susceptibility in the rat. Genetics 149: 289–299.

33. HaagJD, ShepelLA, KolmanBD, MonsonDM, BentonME, et al. (2003) Congenic rats reveal three independent Copenhagen alleles within the Mcs1 quantitative trait locus that confer resistance to mammary cancer. Cancer Res 63: 5808–5812.

34. WoditschkaS, HaagJD, WallerJL, MonsonDM, HittAA, et al. (2006) Neu-induced retroviral rat mammary carcinogenesis: a novel chemoprevention model for both hormonally responsive and nonresponsive mammary carcinomas. Cancer Res 66: 6884–6891.

35. DunhamI, KundajeA, AldredSF, CollinsPJ, DavisCA, et al. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57–74.

36. LangmeadB, TrapnellC, PopM, SalzbergSL (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10: R25.

37. LiB, DeweyCN (2011) RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12: 323.

38. RobinsonMD, McCarthyDJ, SmythGK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26: 139–140.

39. DekkerJ, RippeK, DekkerM, KlecknerN (2002) Capturing chromosome conformation. Science 295: 1306–1311.

40. TolhuisB, PalstraRJ, SplinterE, GrosveldF, de LaatW (2002) Looping and interaction between hypersensitive sites in the active beta-globin locus. Mol Cell 10: 1453–1465.

41. GouldMN, BielWF, CliftonKH (1977) Morphological and quantitative studies of gland formation from inocula of monodispersed rat mammary cells. Exp Cell Res 107: 405–416.

42. SharmaD, EichelbergMR, HaagJD, MeilahnAL, MuelblMJ, et al. (2012) Effective flow cytometric phenotyping of cells using minimal amounts of antibody. Biotechniques 53: 57–60.

43. EdenE, NavonR, SteinfeldI, LipsonD, YakhiniZ (2009) GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics 10: 48.

44. Huang daW, ShermanBT, LempickiRA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44–57.

45. MillerLD, SmedsJ, GeorgeJ, VegaVB, VergaraL, et al. (2005) An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci U S A 102: 13550–13555.

46. WhitfieldML, GeorgeLK, GrantGD, PerouCM (2006) Common markers of proliferation. Nat Rev Cancer 6: 99–106.

47. ReyalF, van VlietMH, ArmstrongNJ, HorlingsHM, de VisserKE, et al. (2008) A comprehensive analysis of prognostic signatures reveals the high predictive capacity of the proliferation, immune response and RNA splicing modules in breast cancer. Breast Cancer Res 10: R93.

48. DaiH, van't VeerL, LambJ, HeYD, MaoM, et al. (2005) A cell proliferation signature is a marker of extremely poor outcome in a subpopulation of breast cancer patients. Cancer Res 65: 4059–4066.

49. HuZ, FanC, OhDS, MarronJS, HeX, et al. (2006) The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 7: 96.

50. RhodesDR, YuJ, ShankerK, DeshpandeN, VaramballyR, et al. (2004) ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6: 1–6.

51. NathansonKL, WeberBL (2001) “Other” breast cancer susceptibility genes: searching for more holy grail. Hum Mol Genet 10: 715–720.

52. PharoahPD, AntoniouA, BobrowM, ZimmernRL, EastonDF, et al. (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31: 33–36.

53. MavaddatN, AntoniouAC, EastonDF, Garcia-ClosasM (2010) Genetic susceptibility to breast cancer. Mol Oncol 4: 174–191.

54. SzpirerC, SzpirerJ (2007) Mammary cancer susceptibility: human genes and rodent models. Mamm Genome 18: 817–831.

55. LanH, KendziorskiCM, HaagJD, ShepelLA, NewtonMA, et al. (2001) Genetic loci controlling breast cancer susceptibility in the Wistar-Kyoto rat. Genetics 157: 331–339.

56. SamuelsonDJ, AperavichBA, HaagJD, GouldMN (2005) Fine mapping reveals multiple loci and a possible epistatic interaction within the mammary carcinoma susceptibility quantitative trait locus, Mcs5. Cancer Res 65: 9637–9642.

57. SamuelsonDJ, HaagJD, LanH, MonsonDM, ShultzMA, et al. (2003) Physical evidence of Mcs5, a QTL controlling mammary carcinoma susceptibility, in congenic rats. Carcinogenesis 24: 1455–1460.

58. SamuelsonDJ, HesselsonSE, AperavichBA, ZanY, HaagJD, et al. (2007) Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk. Proc Natl Acad Sci U S A 104: 6299–6304.

59. DendekkerAD, XuX, VaughnMD, PuckettAH, GardnerLL, et al. (2012) Rat Mcs1b is concordant to the genome wide association identified breast cancer risk locus at human 5q11.2 and MIER3 is a candidate cancer susceptibility gene. Cancer Res 72(22): 6002–12.

60. SmitsBM, SharmaD, SamuelsonDJ, WoditschkaS, MauB, et al. (2011) The non-protein coding breast cancer susceptibility locus Mcs5a acts in a non-mammary cell-autonomous fashion through the immune system and modulates T-cell homeostasis and functions. Breast Cancer Res 13: R81.

61. ViselA, ZhuY, MayD, AfzalV, GongE, et al. (2010) Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 464: 409–412.

62. GeurtsAM, CostGJ, FreyvertY, ZeitlerB, MillerJC, et al. (2009) Knockout rats via embryo microinjection of zinc-finger nucleases. Science 325: 433.

63. CuiX, JiD, FisherDA, WuY, BrinerDM, et al. (2011) Targeted integration in rat and mouse embryos with zinc-finger nucleases. Nat Biotechnol 29: 64–67.

64. WhiteDE, KurpiosNA, ZuoD, HassellJA, BlaessS, et al. (2004) Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell 6: 159–170.

65. CarrJR, KieferMM, ParkHJ, LiJ, WangZ, et al. (2012) FoxM1 regulates mammary luminal cell fate. Cell Rep 1: 715–729.

66. WangLH, TsaiSY, CookRG, BeattieWG, TsaiMJ, et al. (1989) COUP transcription factor is a member of the steroid receptor superfamily. Nature 340: 163–166.

67. CooneyAJ, TsaiSY, O'MalleyBW, TsaiMJ (1992) Chicken ovalbumin upstream promoter transcription factor (COUP-TF) dimers bind to different GGTCA response elements, allowing COUP-TF to repress hormonal induction of the vitamin D3, thyroid hormone, and retinoic acid receptors. Mol Cell Biol 12: 4153–4163.

68. ZhangLJ, LiuX, GafkenPR, KioussiC, LeidM (2009) A chicken ovalbumin upstream promoter transcription factor I (COUP-TFI) complex represses expression of the gene encoding tumor necrosis factor alpha-induced protein 8 (TNFAIP8). J Biol Chem 284: 6156–6168.

69. DaiK, HussainMM (2012) NR2F1 disrupts synergistic activation of the MTTP gene transcription by HNF-4alpha and HNF-1alpha. J Lipid Res 53: 901–908.

70. KuriharaI, ShibataH, KobayashiS, SudaN, IkedaY, et al. (2005) Ubc9 and Protein Inhibitor of Activated STAT 1 Activate Chicken Ovalbumin Upstream Promoter-Transcription Factor I-mediated Human CYP11B2 Gene Transcription. J Biol Chem 280: 6721–6730.

71. SagamiI, TsaiSY, WangH, TsaiMJ, O'MalleyBW (1986) Identification of two factors required for transcription of the ovalbumin gene. Mol Cell Biol 6: 4259–4267.

72. QiuY, PereiraFA, DeMayoFJ, LydonJP, TsaiSY, et al. (1997) Null mutation of mCOUP-TFI results in defects in morphogenesis of the glossopharyngeal ganglion, axonal projection, and arborization. Genes Dev 11: 1925–1937.

73. ZhouC, QiuY, PereiraFA, CrairMC, TsaiSY, et al. (1999) The nuclear orphan receptor COUP-TFI is required for differentiation of subplate neurons and guidance of thalamocortical axons. Neuron 24: 847–859.

74. ZhouC, TsaiSY, TsaiMJ (2001) COUP-TFI: an intrinsic factor for early regionalization of the neocortex. Genes Dev 15: 2054–2059.

75. TangLS, AlgerHM, LinF, PereiraFA (2005) Dynamic expression of COUP-TFI and COUP-TFII during development and functional maturation of the mouse inner ear. Gene Expr Patterns 5: 587–592.

76. TangLS, AlgerHM, PereiraFA (2006) COUP-TFI controls Notch regulation of hair cell and support cell differentiation. Development 133: 3683–3693.

77. FaedoA, TomassyGS, RuanY, TeichmannH, KraussS, et al. (2008) COUP-TFI coordinates cortical patterning, neurogenesis, and laminar fate and modulates MAPK/ERK, AKT, and beta-catenin signaling. Cereb Cortex 18: 2117–2131.

78. NakaH, NakamuraS, ShimazakiT, OkanoH (2008) Requirement for COUP-TFI and II in the temporal specification of neural stem cells in CNS development. Nat Neurosci 11: 1014–1023.

79. SharovAA, WeinerL, SharovaTY, SiebenhaarF, AtoyanR, et al. (2003) Noggin overexpression inhibits eyelid opening by altering epidermal apoptosis and differentiation. Embo J 22: 2992–3003.

80. TangK, XieX, ParkJI, JamrichM, TsaiS, et al. (2010) COUP-TFs regulate eye development by controlling factors essential for optic vesicle morphogenesis. Development 137: 725–734.

81. KlingeCM, SilverBF, DriscollMD, SathyaG, BambaraRA, et al. (1997) Chicken ovalbumin upstream promoter-transcription factor interacts with estrogen receptor, binds to estrogen response elements and half-sites, and inhibits estrogen-induced gene expression. J Biol Chem 272: 31465–31474.

82. KlingeCM, KaurK, SwansonHI (2000) The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1. Arch Biochem Biophys 373: 163–174.

83. TranP, ZhangXK, SalbertG, HermannT, LehmannJM, et al. (1992) COUP orphan receptors are negative regulators of retinoic acid response pathways. Mol Cell Biol 12: 4666–4676.

84. MetivierR, GayFA, HubnerMR, FlouriotG, SalbertG, et al. (2002) Formation of an hER alpha-COUP-TFI complex enhances hER alpha AF-1 through Ser118 phosphorylation by MAPK. Embo J 21: 3443–3453.

85. KlingeCM (1999) Role of estrogen receptor ligand and estrogen response element sequence on interaction with chicken ovalbumin upstream promoter transcription factor (COUP-TF). J Steroid Biochem Mol Biol 71: 1–19.

86. KimRS, Avivar-ValderasA, EstradaY, BragadoP, SosaMS, et al. (2012) Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer. PLoS One 7: e35569.

87. Al-HajjM, WichaMS, Benito-HernandezA, MorrisonSJ, ClarkeMF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100: 3983–3988.

88. BaumannP, CremersN, KroeseF, OrendG, Chiquet-EhrismannR, et al. (2005) CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis. Cancer Res 65: 10783–10793.

89. AthanassiadouP, GrapsaD, GonidiM, AthanassiadouAM, TsipisA, et al. (2009) CD24 expression has a prognostic impact in breast carcinoma. Pathol Res Pract 205: 524–533.

90. TirkkonenM, JohannssonO, AgnarssonBA, OlssonH, IngvarssonS, et al. (1997) Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res 57: 1222–1227.

91. BergamaschiA, KimYH, WangP, SorlieT, Hernandez-BoussardT, et al. (2006) Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosomes Cancer 45: 1033–1040.

92. JohannsdottirHK, JonssonG, JohannesdottirG, AgnarssonBA, EerolaH, et al. (2006) Chromosome 5 imbalance mapping in breast tumors from BRCA1 and BRCA2 mutation carriers and sporadic breast tumors. Int J Cancer 119: 1052–1060.

93. NetworkCGA (2012) Comprehensive molecular portraits of human breast tumours. Nature 490: 61–70.

94. KruseSW, Suino-PowellK, ZhouXE, KretschmanJE, ReynoldsR, et al. (2008) Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor. PLoS Biol 6: e227.

95. AdamsDJ, BiggsPJ, CoxT, DaviesR, van der WeydenL, et al. (2004) Mutagenic insertion and chromosome engineering resource (MICER). Nat Genet 36: 867–871.

96. SmitsBM, TraunBD, DevriesTL, TranA, SamuelsonD, et al. (2012) An insulator loop resides between the synthetically interacting elements of the human/rat conserved breast cancer susceptibility locus MCS5A/Mcs5a. Nucleic Acids Res 40: 132–147.

97. IrizarryRA, BolstadBM, CollinF, CopeLM, HobbsB, et al. (2003) Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 31: e15.

98. GouldMN, CliftonKH (1977) The survival of mammary cells following irradiation in vivo: a directly generated single-dose-survival curve. Radiat Res 72: 343–352.

99. ZhangR, HaagJD, GouldMN (1991) Quantitating the frequency of initiation and cH-ras mutation in in situ N-methyl-N-nitrosourea-exposed rat mammary gland. Cell Growth Differ 2: 1–6.

100. PorterEH, HewittHB, BlakeER (1973) The transplantation kinetics of tumour cells. Br J Cancer 27: 55–62.