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Mammalian Genome

, Volume 26, Issue 1–2, pp 57–79 | Cite as

In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci

  • Darryl L. Hadsell
  • Louise A. Hadsell
  • Walter Olea
  • Monique Rijnkels
  • Chad J. Creighton
  • Ian Smyth
  • Kieran M. Short
  • Liza L. Cox
  • Timothy C. Cox
Article

Abstract

Genetic background plays a dominant role in mammary gland development and breast cancer (BrCa). Despite this, the role of genetics is only partially understood. This study used strain-dependent variation in an inbred mouse mapping panel, to identify quantitative trait loci (QTL) underlying structural variation in mammary ductal development, and determined if these QTL correlated with genomic intervals conferring BrCa susceptibility in humans. For about half of the traits, developmental variation among the complete set of strains in this study was greater (P < 0.05) than that of previously studied strains, or strains in current common use for mammary gland biology. Correlations were also detected with previously reported variation in mammary tumor latency and metastasis. In-silico genome-wide association identified 20 mammary development QTL (Mdq). Of these, five were syntenic with previously reported human BrCa loci. The most significant (P = 1 × 10−11) association of the study was on MMU6 and contained the genes Plxna4, Plxna4os1, and Chchd3. On MMU5, a QTL was detected (P = 8 × 10−7) that was syntenic to a human BrCa locus on h12q24.5 containing the genes Tbx3 and Tbx5. Intersection of linked SNP (r2 > 0.8) with genomic and epigenomic features, and intersection of candidate genes with gene expression and survival data from human BrCa highlighted several for further study. These results support the conclusion that mammary tumorigenesis and normal ductal development are influenced by common genetic factors and that further studies of genetically diverse mice can improve our understanding of BrCa in humans.

Keywords

Quantitative Trait Locus Mammary Gland Mouse Mammary Tumor Virus Linkage Disequilibrium Block Inbred Mouse Strain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors thank Ms. Elizabeth Lessels for her contribution to the initial phenotyping. Thanks also to Dr. Daniel Gatti for providing advice on the association analysis and for providing R scripts used in processing the SNP dataset in this analysis. Thanks also to Mathew LaCourse for technical assistance related to optical projection tomography, to Dr. John Belmont for providing computing resources for the permutation analysis, and to Fengju Chen for technical assistance related to the mining the human tumor gene expression data. Thanks also to Dr. Jeff Rosen for helpful discussion involving the interpretation of the results, and for valuable suggestions on the manuscript. This Project was supported by NICHD Grant Number 5R21HD059746 (Darryl Hadsell), by USDA/ARS Cooperative Agreement No. 6250-51000-052 (Darryl Hadsell), and by NCI Grant Number P30 CA125123 (Chad Creighton). Ian Smyth holds a Future Fellowship from the Australian Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Supplementary material

335_2014_9551_MOESM1_ESM.tif (4.7 mb)
Figure S1. Image processing steps used in the measurement of quantitative ductal development traits. Wholemount images (A) are processed through a series of steps that allow for the creation of background image (B), a background-subtracted image (C), a manually trimmed, background-subtracted image (D), and a binary image used for detection and measurement of the ductal tree (E). The binary image was then skeletonized (F) so that all ductal segments and branch points could be counted and measured. (TIFF 4767 kb)
335_2014_9551_MOESM2_ESM.tif (280 kb)
Figure S2. Measuring quantitative traits for mammary ductal development in mouse mammary gland wholemounts. Mammary wholemounts are stained with hematoxylin and imaged producing images of (A) a fat pad containing a lymph node (purple oval), ductal epithelium (thick black lines). These images are then processed to segment out all components but the ductal tree (B). Ductal area is measured in square millimeters by measuring the number of pixels that occupy the ductal tree and the using a distance conversion based on a size reference. Ductal Perimeter (C) is measured in millimeters and represents the length (orange) of the line that completely surrounds the ductal tree. The ductal tree is then eroded to a single pixel width skeleton (D, orange) and branch points are identified (black squares). This skeleton was used to count total branches and to measure total ductal length. Branch density was then calculated as the ratio of branch counts to total ductal length. (TIFF 279 kb)
335_2014_9551_MOESM3_ESM.pdf (61 kb)
Table S1. Descriptive statistics, broad-sense heritabilities, and statistical comparisons among individual strains. This table provides an indication of the variability among and within strains and provides a means for differentiating the strains from the population mean through a one-sample T test. (PDF 60 kb)
335_2014_9551_MOESM4_ESM.pdf (46 kb)
Table S2. Comparison of variance estimates for mammary gland development among strains sets. This table compares the variance estimates for 15 ductal development traits among the complete set of 43 strains and subset of these strains that would be consider either classical strains or common current strains in mammary gland biology and indicates significant differences (P < 0.05) among the three sets of strains. (PDF 45 kb)
335_2014_9551_MOESM5_ESM.pdf (49 kb)
Table S3. Analysis of long-range LD between 20 QTL regions associated with mammary ductal development in the MDP. This table gives the r2 for the lead SNP presented in Table 1. (PDF 48 kb)
335_2014_9551_MOESM6_ESM.pdf (90 kb)
Table S4. Amino acid substitutions resulting from high-LD SNP associated with mammary ductal development QTL. A total of 9 high-LD SNP were found to produce non-synonymous substitutions in the coding regions of 5 genes. This table shows the predicted consequences of these substitutions. (PDF 89 kb)
335_2014_9551_MOESM7_ESM.pdf (93 kb)
Table S5. Overlap of high-LD SNP in the 3′ UTR with miR target sites. This table shows miR targets sites that overlap in the 3′UTR of candidate genes. (PDF 93 kb)
335_2014_9551_MOESM8_ESM.pdf (48 kb)
Table S6. Overlap of high-LD SNPs with H3K4me2, STAT5, PgR, and HOMER motifs. This table shows the presence of overlaps between STAT5 and PgR binding sites and HOMER Motifs. (PDF 47 kb)

Video S1. Mammary ductal reconstruction in 3D illustrating local patterning in the CZECHII/EiJ stain at 6 week of age. This video is representative of independent samples from at least 6 animals. (MOV 5418 kb)

Video S2. Mammary ductal reconstruction in 3D illustrating local patterning in the KK/HlJ stain at 6 week of age. This video is representative of independent samples from at least 6 animals. (MOV 5878 kb)

References

  1. Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355PubMedGoogle Scholar
  2. Andres AC, Schonenberger CA, Groner B, Hennighausen L, LeMeur M, Gerlinger P (1987) Ha-ras oncogene expression directed by a milk protein gene promoter: tissue specificity, hormonal regulation, and tumor induction in transgenic mice. Proc Natl Acad Sci USA 84:1299–1303PubMedCentralPubMedGoogle Scholar
  3. Apolant H (1906) Die epithelian geschwulste des maus. Arbeiten Koniglchn Ins Exp The Zu Frankfurt 1:61Google Scholar
  4. Atwood CS, Hovey RC, Glover JP, Chepko G, Ginsburg E, Robison WG, Vonderhaar BK (2000) Progesterone induces side-branching of the ductal epithelium in the mammary glands of peripubertal mice. J Endocrinol 167:39–52PubMedGoogle Scholar
  5. Aumailley M (2013) The laminin family. Cell Adh Migr 7:48–55PubMedCentralPubMedGoogle Scholar
  6. Aupperlee MD, Drolet AA, Durairaj S, Wang W, Schwartz RC, Haslam SZ (2009) Strain-specific differences in the mechanisms of progesterone regulation of murine mammary gland development. Endocrinology 150:1485–1494PubMedCentralPubMedGoogle Scholar
  7. Bamshad M, Lin RC, Law DJ, Watkins WC, Krakowiak PA, Moore ME, Franceschini P, Lala R, Holmes LB, Gebuhr TC, Bruneau BG, Schinzel A, Seidman JG, Seidman CE, Jorde LB (1997) Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet 16:311–315PubMedGoogle Scholar
  8. Bamshad M, Le T, Watkins WS, Dixon ME, Kramer BE, Roeder AD, Carey JC, Root S, Schinzel A, Van Maldergem L, Gardner RJ, Lin RC, Seidman CE, Seidman JG, Wallerstein R, Moran E, Sutphen R, Campbell CE, Jorde LB (1999) The spectrum of mutations in TBX3: genotype/phenotype relationship in ulnar-mammary syndrome. Am J Hum Genet 64:1550–1562PubMedCentralPubMedGoogle Scholar
  9. Baple EL, Chambers H, Cross HE, Fawcett H, Nakazawa Y, Chioza BA, Harlalka GV, Mansour S, Sreekantan-Nair A, Patton MA, Muggenthaler M, Rich P, Wagner K, Coblentz R, Stein CK, Last JI, Taylor AM, Jackson AP, Ogi T, Lehmann AR, Green CM, Crosby AH (2014) Hypomorphic PCNA mutation underlies a human DNA repair disorder. J Clin Invest 124:3137–3146PubMedCentralPubMedGoogle Scholar
  10. Bean SL, C., Swing SP, Macauley M, Neleski L (2000) C3H strains free of exongenous mmtv. JAX Notes 480, 1Google Scholar
  11. Betts MJ, Russell RB (2003) Amino acid properties and consequences of substitutions. In: Barnes MR, Gray IC (eds) Bioinformatics for geneticists. Wiley, New YorkGoogle Scholar
  12. Bhattacharya A, Ziebarth JD, Cui Y (2014) PolymiRTS Database 3.0: linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways. Nucleic Acids Res 42:D86–D91PubMedCentralPubMedGoogle Scholar
  13. Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, Karczewski KJ, Park J, Hitz BC, Weng S, Cherry JM, Snyder M (2012) Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 22:1790–1797PubMedCentralPubMedGoogle Scholar
  14. Brewster BL, Rossiello F, French JD, Edwards SL, Wong M, Wronski A, Whiley P, Waddell N, Chen X, Bove B, Hopper JL, John EM, Andrulis I, Daly M, Volorio S, Bernard L, Peissel B, Manoukian S, Barile M, Pizzamiglio S, Verderio P, Spurdle AB, Radice P, Godwin AK, Southey MC, Brown MA, Peterlongo P (2012) Identification of fifteen novel germline variants in the BRCA1 3′UTR reveals a variant in a breast cancer case that introduces a functional miR-103 target site. Hum Mutat 33:1665–1675PubMedGoogle Scholar
  15. Brunschwig H, Levi L, Ben-David E, Williams RW, Yakir B, Shifman S (2012) Fine-scale maps of recombination rates and hotspots in the mouse genome. Genetics 191:757–764PubMedCentralPubMedGoogle Scholar
  16. Brunskill EW, Georgas K, Rumballe B, Little MH, Potter SS (2011) Defining the molecular character of the developing and adult kidney podocyte. PLoS ONE 6:e24640PubMedCentralPubMedGoogle Scholar
  17. Buhler TA, Dale TC, Kieback C, Humphreys RC, Rosen JM (1993) Localization and quantification of Wnt-2 gene expression in mouse mammary development. Dev Biol 155:87–96PubMedGoogle Scholar
  18. Burgess-Herbert SL, Tsaih SW, Stylianou IM, Walsh K, Cox AJ, Paigen B (2009) An experimental assessment of in silico haplotype association mapping in laboratory mice. BMC Genet 10:81PubMedCentralPubMedGoogle Scholar
  19. Castellana B, Escuin D, Perez-Olabarria M, Vazquez T, Munoz J, Peiro G, Barnadas A, Lerma E (2012) Genetic up-regulation and overexpression of PLEKHA7 differentiates invasive lobular carcinomas from invasive ductal carcinomas. Hum Pathol 43:1902–1909PubMedGoogle Scholar
  20. Cervino AC, Li G, Edwards S, Zhu J, Laurie C, Tokiwa G, Lum PY, Wang S, Castellini LW, Lusis AJ, Carlson S, Sachs AB, Schadt EE (2005) Integrating QTL and high-density SNP analyses in mice to identify Insig2 as a susceptibility gene for plasma cholesterol levels. Genomics 86:505–517PubMedGoogle Scholar
  21. Chakravarty G, Hadsell D, Buitrago W, Settleman J, Rosen JM (2003) p190-B RhoGAP regulates mammary ductal morphogenesis. Mol Endocrinol 17:1054–1065PubMedGoogle Scholar
  22. Chang SH, Jobling S, Brennan K, Headon DJ (2009) Enhanced Edar signalling has pleiotropic effects on craniofacial and cutaneous glands. PLoS ONE 4:e7591PubMedCentralPubMedGoogle Scholar
  23. Chen CY, Chang IS, Hsiung CA, Wasserman WW (2014) On the identification of potential regulatory variants within genome wide association candidate SNP sets. BMC Med Genomics 7:34PubMedCentralPubMedGoogle Scholar
  24. Cho KW, Kwon HJ, Shin JO, Lee JM, Cho SW, Tickle C, Jung HS (2012) Retinoic acid signaling and the initiation of mammary gland development. Dev Biol 365:259–266PubMedGoogle Scholar
  25. Churchill GA, Doerge RW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138:963–971PubMedCentralPubMedGoogle Scholar
  26. Davenport TG, Jerome-Majewska LA, Papaioannou VE (2003) Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development 130:2263–2273PubMedGoogle Scholar
  27. Davis RC, van Nas A, Bennett B, Orozco L, Pan C, Rau CD, Eskin E, Lusis AJ (2013) Genome-wide association mapping of blood cell traits in mice. Mamm Genome 24:105–118PubMedCentralPubMedGoogle Scholar
  28. Douglas NC, Papaioannou VE (2013) The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia 18:143–147PubMedCentralPubMedGoogle Scholar
  29. Eblaghie MC, Song SJ, Kim JY, Akita K, Tickle C, Jung HS (2004) Interactions between FGF and Wnt signals and Tbx3 gene expression in mammary gland initiation in mouse embryos. J Anat 205:1–13PubMedCentralPubMedGoogle Scholar
  30. Fernandez-Gonzalez R, Barcellos-Hoff MH, Ortiz-de-Solorzano C (2004) Quantitative image analysis in mammary gland biology. J Mammary Gland Biol Neoplasia 9:343–359PubMedGoogle Scholar
  31. Filipek A (2006) S100A6 and CacyBP/SIP—two proteins discovered in ehrlich ascites tumor cells that are potentially involved in the degradation of beta-catenin. Chemotherapy 52:32–34PubMedGoogle Scholar
  32. Finlay AY, Marks R (1978) An hereditary syndrome of lumpy scalp, odd ears and rudimentary nipples. Br J Dermatol 99:423–430PubMedGoogle Scholar
  33. Flux DS (1954) Growth of the mammary duct system in intact and ovariectomized mice of the CHI strain. J Endocrinol 11:223–237PubMedGoogle Scholar
  34. Frazer KA, Eskin E, Kang HM, Bogue MA, Hinds DA, Beilharz EJ, Gupta RV, Montgomery J, Morenzoni MM, Nilsen GB, Pethiyagoda CL, Stuve LL, Johnson FM, Daly MJ, Wade CM, Cox DR (2007) A sequence-based variation map of 8.27 million SNPs in inbred mouse strains. Nature 448:1050–1053PubMedGoogle Scholar
  35. Fuseler JW, Robichaux JP, Atiyah HI, Ramsdell AF (2014) Morphometric and fractal dimension analysis identifies early neoplastic changes in mammary epithelium of MMTV-cNeu mice. Anticancer Res 34:1171–1177PubMedGoogle Scholar
  36. Gardner WU, Strong LC (1935) The normal development of the mammary glands of virgin female mice of ten strains varying in susceptibility to spontaneous neoplasms. Am J Cancer 25:285–290Google Scholar
  37. Ghabrial AS, Levi BP, Krasnow MA (2011) A systematic screen for tube morphogenesis and branching genes in the Drosophila tracheal system. PLoS Genet 7:e1002087PubMedCentralPubMedGoogle Scholar
  38. Ghazalpour A, Rau CD, Farber CR, Bennett BJ, Orozco LD, van Nas A, Pan C, Allayee H, Beaven SW, Civelek M, Davis RC, Drake TA, Friedman RA, Furlotte N, Hui ST, Jentsch JD, Kostem E, Kang HM, Kang EY, Joo JW, Korshunov VA, Laughlin RE, Martin LJ, Ohmen JD, Parks BW, Pellegrini M, Reue K, Smith DJ, Tetradis S, Wang J, Wang Y, Weiss JN, Kirchgessner T, Gargalovic PS, Eskin E, Lusis AJ, LeBoeuf RC (2012) Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits. Mamm Genome 23:680–692PubMedCentralPubMedGoogle Scholar
  39. Ghoussaini M, Pharoah PD, Easton DF (2013) Inherited genetic susceptibility to breast cancer: the beginning of the end or the end of the beginning? Am J Pathol 183:1038–1051PubMedGoogle Scholar
  40. Gibson LM (1930) A comparative study of the life history of the female mammaryg gland in two strains of albino mice. Cancer Res 14:31Google Scholar
  41. Gjorevski N, Nelson CM (2011) Integrated morphodynamic signalling of the mammary gland. Nat Rev Mol Cell Biol 12:581–593PubMedGoogle Scholar
  42. Grupe A, Germer S, Usuka J, Aud D, Belknap JK, Klein RF, Ahluwalia MK, Higuchi R, Peltz G (2001) In silico mapping of complex disease-related traits in mice. Science 292:1915–1918PubMedGoogle Scholar
  43. Haaland M (1911) Spontaneous tumors in mice. In: Bashford EF (ed) Fourth scientific report on the investigations of the imperial cancer research fund. Imperial Cancer Research Fund, London, pp 1–113Google Scholar
  44. Heckman BM, Chakravarty G, Vargo-Gogola T, Gonzales-Rimbau M, Hadsell DL, Lee AV, Settleman J, Rosen JM (2007) Crosstalk between the p190-B RhoGAP and IGF signaling pathways is required for embryonic mammary bud development. Dev Biol 309:137–149PubMedCentralPubMedGoogle Scholar
  45. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38:576–589PubMedCentralPubMedGoogle Scholar
  46. Højsgaard S, Halekoh U, Robinson-Cox J, Wright K, Leidi AA (2013) doBy—groupwise summary statistics, general linerar constrasts, population means (least-squares-means), and other utilities, R package version 4.5-8. http://CRAN.R-project.org/package=doBy
  47. Hong H, Yen HY, Brockmeyer A, Liu Y, Chodankar R, Pike MC, Stanczyk FZ, Maxson R, Dubeau L (2010) Changes in the mouse estrus cycle in response to BRCA1 inactivation suggest a potential link between risk factors for familial and sporadic ovarian cancer. Cancer Res 70:221–228PubMedCentralPubMedGoogle Scholar
  48. Howard BA, Gusterson BA (2000a) The characterization of a mouse mutant that displays abnormal mammary gland development. Mamm Genome 11:234–237PubMedGoogle Scholar
  49. Howard BA, Gusterson BA (2000b) Mammary gland patterning in the AXB/BXA recombinant inbred strains of mouse. Mech Dev 91:305–309PubMedGoogle Scholar
  50. Howard B, Panchal H, McCarthy A, Ashworth A (2005) Identification of the scaramanga gene implicates Neuregulin3 in mammary gland specification. Genes Dev 19:2078–2090PubMedCentralPubMedGoogle Scholar
  51. Hunter KW (2004) Host genetics and tumour metastasis. Br J Cancer 90:752–755PubMedCentralPubMedGoogle Scholar
  52. Hunter KW (2012) Mouse models of cancer: does the strain matter? Nat Rev Cancer 12:144–149PubMedGoogle Scholar
  53. Huseby RA, Bittner JJ (1946) A comparative morphological study of the mammary glands with reference to the known factors influencing the development of mammary carcinoma in mice. Cancer Res 6:240–255PubMedGoogle Scholar
  54. Kamikawa A, Ichii O, Yamaji D, Imao T, Suzuki C, Okamatsu-Ogura Y, Terao A, Kon Y, Kimura K (2009) Diet-induced obesity disrupts ductal development in the mammary glands of nonpregnant mice. Dev Dyn 238:1092–1099PubMedGoogle Scholar
  55. Kang HM, Zaitlen NA, Wade CM, Kirby A, Heckerman D, Daly MJ, Eskin E (2008) Efficient control of population structure in model organism association mapping. Genetics 178:1709–1723PubMedCentralPubMedGoogle Scholar
  56. Kendrick H, Regan JL, Magnay FA, Grigoriadis A, Mitsopoulos C, Zvelebil M, Smalley MJ (2008) Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate. BMC Genom 9:591Google Scholar
  57. Kessler JD, Kahle KT, Sun T, Meerbrey KL, Schlabach MR, Schmitt EM, Skinner SO, Xu Q, Li MZ, Hartman ZC, Rao M, Yu P, Dominguez-Vidana R, Liang AC, Solimini NL, Bernardi RJ, Yu B, Hsu T, Golding I, Luo J, Osborne CK, Creighton CJ, Hilsenbeck SG, Schiff R, Shaw CA, Elledge SJ, Westbrook TF (2012) A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science 335:348–353PubMedCentralPubMedGoogle Scholar
  58. Kirby A, Kang HM, Wade CM, Cotsapas CJ, Kostem E, Han B, Furlotte N, Kang EY, Rivas M, Bogue MA, Frazer KA, Johnson FM, Beilharz EJ, Cox DR, Eskin E, Daly MJ (2010) Fine mapping in 94 inbred mouse strains using a high-density haplotype resource. Genetics 185(3):1081–1095Google Scholar
  59. Klinowska TC, Soriano JV, Edwards GM, Oliver JM, Valentijn AJ, Montesano R, Streuli CH (1999) Laminin and beta1 integrins are crucial for normal mammary gland development in the mouse. Dev Biol 215:13–32PubMedGoogle Scholar
  60. Kohl M (2011) MKmisc: miscellaneous functions from M. Kohl, R package version 0.9. http://www.stamats.de
  61. Kouros-Mehr H, Werb Z (2006) Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn 235:3404–3412PubMedCentralPubMedGoogle Scholar
  62. Kurita S, Yamada T, Rikitsu E, Ikeda W, Takai Y (2013) Binding between the junctional proteins afadin and PLEKHA7 and implication in the formation of adherens junction in epithelial cells. J Biol Chem 288:29356–29368PubMedCentralPubMedGoogle Scholar
  63. Lain AR, Creighton CJ, Conneely OM (2013) Research resource: progesterone receptor targetome underlying mammary gland branching morphogenesis. Mol Endocrinol 27:1743–1761PubMedCentralPubMedGoogle Scholar
  64. Larive RM, Abad A, Cardaba CM, Hernandez T, Canamero M, de Alava E, Santos E, Alarcon B, Bustelo XR (2012) The Ras-like protein R-Ras2/TC21 is important for proper mammary gland development. Mol Biol Cell 23:2373–2387PubMedCentralPubMedGoogle Scholar
  65. Li MJ, Wang P, Liu X, Lim EL, Wang Z, Yeager M, Wong MP, Sham PC, Chanock SJ, Wang J (2012) GWASdb: a database for human genetic variants identified by genome-wide association studies. Nucleic Acids Res 40:D1047–D1054PubMedCentralPubMedGoogle Scholar
  66. Lifsted T, Le Voyer T, Williams M, Muller W, Klein-Szanto A, Buetow KH, Hunter KW (1998) Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression. Int J Cancer 77:640–644PubMedGoogle Scholar
  67. Lydon JP, Ge G, Kittrell FS, Medina D, O’Malley BW (1999) Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function. Cancer Res 59:4276–4284PubMedGoogle Scholar
  68. Macintyre G, Bailey J, Haviv I, Kowalczyk A (2010) is-rSNP: a novel technique for in silico regulatory SNP detection. Bioinformatics 26:i524–i530PubMedCentralPubMedGoogle Scholar
  69. Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, Reynolds AP, Sandstrom R, Qu H, Brody J, Shafer A, Neri F, Lee K, Kutyavin T, Stehling-Sun S, Johnson AK, Canfield TK, Giste E, Diegel M, Bates D, Hansen RS, Neph S, Sabo PJ, Heimfeld S, Raubitschek A, Ziegler S, Cotsapas C, Sotoodehnia N, Glass I, Sunyaev SR, Kaul R, Stamatoyannopoulos JA (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337:1190–1195PubMedCentralPubMedGoogle Scholar
  70. McCleland ML, Kallio MJ, Barrett-Wilt GA, Kestner CA, Shabanowitz J, Hunt DF, Gorbsky GJ, Stukenberg PT (2004) The vertebrate Ndc80 complex contains Spc24 and Spc25 homologs, which are required to establish and maintain kinetochore-microtubule attachment. Curr Biol 14:131–137PubMedGoogle Scholar
  71. McNally S, Martin F (2011) Molecular regulators of pubertal mammary gland development. Ann Med 43:212–234PubMedGoogle Scholar
  72. Medina D (2010) Of mice and women: a short history of mouse mammary cancer research with an emphasis on the paradigms inspired by the transplantation method. Cold Spring Harb Perspect Biol 2:a004523PubMedCentralPubMedGoogle Scholar
  73. Megarbane H, Cluzeau C, Bodemer C, Fraitag S, Chababi-Atallah M, Megarbane A, Smahi A (2008) Unusual presentation of a severe autosomal recessive anhydrotic ectodermal dysplasia with a novel mutation in the EDAR gene. Am J Med Genet A 146A:2657–2662PubMedGoogle Scholar
  74. Metzger RJ, Klein OD, Martin GR, Krasnow MA (2008) The branching programme of mouse lung development. Nature 453:745–750PubMedCentralPubMedGoogle Scholar
  75. Miller BH, Schultz LE, Gulati A, Su AI, Pletcher MT (2010) Phenotypic characterization of a genetically diverse panel of mice for behavioral despair and anxiety. PLoS ONE 5:e14458PubMedCentralPubMedGoogle Scholar
  76. Miller TW, Rexer BN, Garrett JT, Arteaga CL (2011) Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res 13:224PubMedCentralPubMedGoogle Scholar
  77. Morris JS, Stein T, Pringle MA, Davies CR, Weber-Hall S, Ferrier RK, Bell AK, Heath VJ, Gusterson BA (2006) Involvement of axonal guidance proteins and their signaling partners in the developing mouse mammary gland. J Cell Physiol 206:16–24PubMedGoogle Scholar
  78. Mulac-Jericevic B, Lydon JP, DeMayo FJ, Conneely OM (2003) Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci USA 100:9744–9749PubMedCentralPubMedGoogle Scholar
  79. Naylor MJ, Ormandy CJ (2002) Mouse strain-specific patterns of mammary epithelial ductal side branching are elicited by stromal factors. Dev Dyn 225:100–105PubMedGoogle Scholar
  80. Neuwirth E (2007) RColorBrewer: ColorBrewer palettes. R package version 1.0-2Google Scholar
  81. Ochoa-Espinosa A, Affolter M (2012) Branching morphogenesis: from cells to organs and back. Cold Spring Harb Perspect Biol 4:1–14Google Scholar
  82. Ohta K, Takagi S, Asou H, Fujisawa H (1992) Involvement of neuronal cell surface molecule B2 in the formation of retinal plexiform layers. Neuron 9:151–161PubMedGoogle Scholar
  83. Okazaki M, Kishida S, Murai H, Hinoi T, Kikuchi A (1996) Ras-interacting domain of Ral GDP dissociation stimulator like (RGL) reverses v-Ras-induced transformation and Raf-1 activation in NIH3T3 cells. Cancer Res 56:2387–2392PubMedGoogle Scholar
  84. Olson LK, Tan Y, Zhao Y, Aupperlee MD, Haslam SZ (2010) Pubertal exposure to high fat diet causes mouse strain-dependent alterations in mammary gland development and estrogen responsiveness. Int J Obes (Lond) 34:1415–1426Google Scholar
  85. Owen BM, Bookout AL, Ding X, Lin VY, Atkin SD, Gautron L, Kliewer SA, Mangelsdorf DJ (2013) FGF21 contributes to neuroendocrine control of female reproduction. Nat Med 19:1153–1156PubMedCentralPubMedGoogle Scholar
  86. Paul DS, Albers CA, Rendon A, Voss K, Stephens J, van der Harst P, Chambers JC, Soranzo N, Ouwehand WH, Deloukas P (2013) Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci. Genome Res 23:1130–1141PubMedCentralPubMedGoogle Scholar
  87. Perala N, Sariola H, Immonen T (2012) More than nervous: the emerging roles of plexins. Differentiation 83:77–91PubMedGoogle Scholar
  88. Peto J, Mack TM (2000) High constant incidence in twins and other relatives of women with breast cancer. Nat Genet 26:411–414PubMedGoogle Scholar
  89. Pletcher MT, McClurg P, Batalov S, Su AI, Barnes SW, Lagler E, Korstanje R, Wang X, Nusskern D, Bogue MA, Mural RJ, Paigen B, Wiltshire T (2004) Use of a dense single nucleotide polymorphism map for in silico mapping in the mouse. PLoS Biol 2:e393PubMedCentralPubMedGoogle Scholar
  90. Propper AY, Howard BA, Veltmaat JM (2013) Prenatal morphogenesis of mammary glands in mouse and rabbit. J Mammary Gland Biol Neoplasia 18:93–104PubMedCentralPubMedGoogle Scholar
  91. Rasmussen SBY, Young LJT, Smith GH (2000) Preparing mammary gland whole mounts from mice. In: Ip BB, Asch MM (eds) Methods in mammary gland biology and breast cancer research. Kluwer Academic/Plenum Publishers, New YorkGoogle Scholar
  92. Richert MM, Schwertfeger KL, Ryder JW, Anderson SM (2000) An atlas of mouse mammary gland development. J Mammary Gland Biol Neoplasia 5:227–241PubMedGoogle Scholar
  93. Rijnkels M, Freeman-Zadrowski C, Hernandez J, Potluri V, Wang L, Li W, Lemay DG (2013) Epigenetic modifications unlock the milk protein gene loci during mouse mammary gland development and differentiation. PLoS ONE 8:e53270PubMedCentralPubMedGoogle Scholar
  94. Robichaux JP, Hallett RM, Fuseler JW, Hassell JA, Ramsdell AF (2014) Mammary glands exhibit molecular laterality and undergo left-right asymmetric ductal epithelial growth in MMTV-cNeu mice*. Oncogene. doi: 10.1038/onc.2014.149
  95. Rogozin IB, Basu MK, Jordan IK, Pavlov YI, Koonin EV (2005) APOBEC4, a new member of the AID/APOBEC family of polynucleotide (deoxy)cytidine deaminases predicted by computational analysis. Cell Cycle 4:1281–1285PubMedGoogle Scholar
  96. Sakakura T, Suzuki Y, Shiurba R (2013) Mammary stroma in development and carcinogenesis. J Mammary Gland Biol Neoplasia 18:189–197PubMedGoogle Scholar
  97. Sethupathy P, Collins FS (2008) MicroRNA target site polymorphisms and human disease. Trends Genet 24:489–497PubMedGoogle Scholar
  98. Short K, Hodson M, Smyth I (2013) Spatial mapping and quantification of developmental branching morphogenesis. Development 140:471–478PubMedGoogle Scholar
  99. Short KM, Combes AN, Lefevre J, Ju AL, Georgas KM, Lamberton T, Cairncross O, Rumballe BA, McMahon AP, Hamilton NA, Smyth IM, Little MH (2014) Global quantification of tissue dynamics in the developing mouse kidney. Dev Cell 29:188–202PubMedGoogle Scholar
  100. Silberstein GB (2001) Postnatal mammary gland morphogenesis. Microsc Res Tech 52:155–162PubMedGoogle Scholar
  101. Sternlicht MD (2006) Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis. Breast Cancer Res 8:201PubMedCentralPubMedGoogle Scholar
  102. Stover BC, Muller KF (2010) TreeGraph 2: combining and visualizing evidence from different phylogenetic analyses. BMC Bioinformatics 11:7PubMedCentralPubMedGoogle Scholar
  103. Tang PL, Cheung CL, Sham PC, McClurg P, Lee B, Chan SY, Smith DK, Tanner JA, Su AI, Cheah KS, Kung AW, Song YQ (2009) Genome-wide haplotype association mapping in mice identifies a genetic variant in CER1 associated with BMD and fracture in southern Chinese women. J Bone Miner Res 24:1013–1021PubMedGoogle Scholar
  104. Team RDC (2010) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  105. Thomas-Chollier M, Hufton A, Heinig M, O’Keeffe S, Masri NE, Roider HG, Manke T, Vingron M (2011) Transcription factor binding predictions using TRAP for the analysis of ChIP-seq data and regulatory SNPs. Nat Protoc 6:1860–1869PubMedGoogle Scholar
  106. van Bokhoven H, Hamel BC, Bamshad M, Sangiorgi E, Gurrieri F, Duijf PH, Vanmolkot KR, van Beusekom E, van Beersum SE, Celli J, Merkx GF, Tenconi R, Fryns JP, Verloes A, Newbury-Ecob RA, Raas-Rotschild A, Majewski F, Beemer FA, Janecke A, Chitayat D, Crisponi G, Kayserili H, Yates JR, Neri G, Brunner HG (2001) p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet 69:481–492PubMedCentralPubMedGoogle Scholar
  107. van Genderen C, Okamura RM, Farinas I, Quo RG, Parslow TG, Bruhn L, Grosschedl R (1994) Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev 8:2691–2703PubMedGoogle Scholar
  108. van Steensel MA, Celli J, van Bokhoven JH, Brunner HG (1999) Probing the gene expression database for candidate genes. Eur J Hum Genet 7:910–919PubMedGoogle Scholar
  109. Vargo-Gogola T, Heckman BM, Gunther EJ, Chodosh LA, Rosen JM (2006) P190-B Rho GTPase-activating protein overexpression disrupts ductal morphogenesis and induces hyperplastic lesions in the developing mammary gland. Mol Endocrinol 20:1391–1405PubMedGoogle Scholar
  110. Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40:D930–D934PubMedCentralPubMedGoogle Scholar
  111. Warnes GR, Bolker B, Bonebakker L, Gentleman R, Liaw WHA, Lumley T, Maechler M, Magnusson A, Moeller S, Schwartz M, Venables B (2011) gplots: Various R programming tools for plotting data, R package version 2.10.1. http://CRAN.R-project.org/package=gplots
  112. Yamaji D, Kang K, Robinson GW, Hennighausen L (2013) Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration. Nucleic Acids Res 41:1622–1636PubMedCentralPubMedGoogle Scholar
  113. Yant J, Gusterson B, Kamalati T (1998) Induction of strain-specific mouse mammary gland ductal architecture. The Breast 7:4Google Scholar
  114. Yuan R, Meng Q, Nautiyal J, Flurkey K, Tsaih SW, Krier R, Parker MG, Harrison DE, Paigen B (2012) Genetic coregulation of age of female sexual maturation and lifespan through circulating IGF1 among inbred mouse strains. Proc Natl Acad Sci USA 109:8224–8229PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Darryl L. Hadsell
    • 1
    • 2
  • Louise A. Hadsell
    • 1
  • Walter Olea
    • 1
  • Monique Rijnkels
    • 3
  • Chad J. Creighton
    • 4
  • Ian Smyth
    • 5
    • 6
  • Kieran M. Short
    • 6
  • Liza L. Cox
    • 7
    • 8
  • Timothy C. Cox
    • 7
    • 8
  1. 1.Department of Pediatrics, USDA/ARS Children’s Nutrition Research CenterBaylor College of MedicineHoustonUSA
  2. 2.Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonUSA
  3. 3.Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical SciencesTexas A&M UniversityCollege StationUSA
  4. 4.Division of Biostatistics, Department of Medicine, Dan L. Duncan Cancer CenterBaylor College of MedicineHoustonUSA
  5. 5.Department of Anatomy and Developmental BiologyMonash University, ClaytonClaytonAustralia
  6. 6.Department of Biochemistry and Molecular BiologyMonash University, ClaytonClaytonAustralia
  7. 7.Department of PediatricsUniversity of Washington School of MedicineSeattleUSA
  8. 8.Center for Developmental Biology and Regenerative MedicineSeattle Children’s Research InstituteSeattleUSA

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