Abstract
Mouse mammary gland involution resembles a wound healing response with suppressed inflammation. Wound healing and inflammation are also associated with tumour development, and a ‘wound-healing’ gene expression signature can predict metastasis formation and survival. Recent studies have shown that an involuting mammary gland stroma can promote metastasis. It could therefore be hypothesised that gene expression signatures from an involuting mouse mammary gland may provide new insights into the physiological pathways that promote breast cancer progression. Indeed, using the HOPACH clustering method, the human orthologues of genes that were differentially regulated at day 3 of mammary gland involution and showed prolonged expression throughout the first 4 days of involution distinguished breast cancers in the NKI 295 breast cancer dataset with low and high metastatic activity. Most strikingly, genes associated with copper ion homeostasis and with HIF-1 promoter binding sites were the most over-represented, linking this signature to hypoxia. Further, six out of the ten mRNAs with strongest up-regulation in cancers with poor survival code for secreted factors, identifying potential candidates that may be involved in stromal/matrix-enhanced metastasis formation/breast cancer development. This method therefore identified biological processes that occur during mammary gland involution, which may be critical in promoting breast cancer metastasis that could form a basis for future investigation, and supports a role for copper in breast cancer development.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10911-009-9120-1/MediaObjects/10911_2009_9120_Fig1_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10911-009-9120-1/MediaObjects/10911_2009_9120_Fig2_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10911-009-9120-1/MediaObjects/10911_2009_9120_Fig3_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10911-009-9120-1/MediaObjects/10911_2009_9120_Fig4_HTML.gif)
Similar content being viewed by others
Abbreviations
- AP-1:
-
activator protein 1
- CI:
-
confidence interval
- bHLH-Zip:
-
basic helix-loop-helix protein with leucine zipper
- DCIS:
-
ductal carcinoma in situ
- EGF:
-
epidermal growth factor
- ER:
-
oestrogen receptor
- ErbB2:
-
erythroblastic leukemia viral oncogene homologue 2
- GC-RMA:
-
robust multi-array expression measure using GC-content information
- GenMAPP:
-
gene map annotator and pathway profiler
- GO:
-
Gene Ontology
- HER2:
-
Human EGF receptor 2
- HIF:
-
hypoxia-inducible factor
- HOPACH:
-
hierarchical ordered partitioning and collapsing hybrid
- HR:
-
hazard ratio
- IGF-1:
-
Insulin-like growth factor
- IGFBP5:
-
IGF-binding protein 5
- LPS:
-
lipopolysaccharide
- Neu:
-
neuro/glioblastoma derived oncogene homolog (avian)
- PANTHER:
-
protein analysis through evolutionary relationships
- PgR:
-
progesterone receptor
- TGF:
-
transforming growth factor
- VEGF:
-
vascular endothelial growth factor
References
Clarkson RW, Wayland MT, Lee J, Freeman T, Watson CJ. Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression. Breast Cancer Res. 2004;6:R92–109. doi:10.1186/bcr754.
Stein T, Morris JS, Davies CR, Weber-Hall SJ, Duffy MA, Heath VJ, et al. Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3. Breast Cancer Res. 2004;6:R75–91. doi:10.1186/bcr753.
Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7. doi:10.1038/nature01322.
Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315:1650–9.
McDaniel SM, Rumer KK, Biroc SL, Metz RP, Singh M, Porter W, et al. Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. Am J Pathol. 2006;168:608–20. doi:10.2353/ajpath.2006.050677.
Schedin P, O'Brien J, Rudolph M, Stein T, Borges V. Microenvironment of the involuting mammary gland mediates mammary cancer progression. J Mammary Gland Biol Neoplasia. 2007;12:71–82. doi:10.1007/s10911-007-9039-3.
Chang HY, Nuyten DS, Sneddon JB, Hastie T, Tibshirani R, Sorlie T, et al. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci USA. 2005;102:3738–43. doi:10.1073/pnas.0409462102.
Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K, et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol. 2004;2:E7. doi:10.1371/journal.pbio.0020007.
Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME, Salim A, et al. Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med. 2006;3:e47. doi:10.1371/journal.pmed.0030047.
Dai H, van't Veer L, Lamb J, He YD, Mao M, Fine BM, et al. A cell proliferation signature is a marker of extremely poor outcome in a subpopulation of breast cancer patients. Cancer Res. 2005;65:4059–66. doi:10.1158/0008-5472.CAN-04-3953.
Foekens JA, Atkins D, Zhang Y, Sweep FC, Harbeck N, Paradiso A, et al. Multicenter validation of a gene expression-based prognostic signature in lymph node-negative primary breast cancer. J Clin Oncol. 2006;24:1665–71. doi:10.1200/JCO.2005.03.9115.
Oh DS, Troester MA, Usary J, Hu Z, He X, Fan C, et al. Estrogen-regulated genes predict survival in hormone receptor-positive breast cancers. J Clin Oncol. 2006;24:1656–64. doi:10.1200/JCO.2005.03.2755.
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52. doi:10.1038/35021093.
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;98:10869–74. doi:10.1073/pnas.191367098.
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;100:8418–23. doi:10.1073/pnas.0932692100.
Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA. 2003;100:10393–8. doi:10.1073/pnas.1732912100.
Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, et al. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst. 2006;98:262–72.
van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530–6. doi:10.1038/415530a.
Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet. 2005;365:671–9.
West RB, Nuyten DS, Subramanian S, Nielsen TO, Corless CL, Rubin BP, et al. Determination of stromal signatures in breast carcinoma. PLoS Biol. 2005;3:e187. doi:10.1371/journal.pbio.0030187.
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;347:1999–2009. doi:10.1056/NEJMoa021967.
Salomonis N, Cotte N, Zambon AC, Pollard KS, Vranizan K, Doniger SW, et al. Identifying genetic networks underlying myometrial transition to labor. Genome Biol. 2005;6:R12. doi:10.1186/gb-2005-6-2-r12.
Doniger SW, Salomonis N, Dahlquist KD, Vranizan K, Lawlor SC, Conklin BR. MAPPFinder: using Gene Ontology and GenMAPP to create a global gene-expression profile from microarray data. Genome Biol. 2003;4:R7. doi:10.1186/gb-2003-4-1-r7.
Dahlquist KD, Salomonis N, Vranizan K, Lawlor SC, Conklin BR. GenMAPP, a new tool for viewing and analyzing microarray data on biological pathways. Nat Genet. 2002;31:19–20. doi:10.1038/ng0502-19.
Mi H, Guo N, Kejariwal A, Thomas PD. PANTHER version 6: protein sequence and function evolution data with expanded representation of biological pathways. Nucleic Acids Res. 2007;35:D247–52. doi:10.1093/nar/gkl869.
Hermann LM, Pinkerton M, Jennings K, Yang L, Grom A, Sowders D, et al. Angiopoietin-like-4 is a potential angiogenic mediator in arthritis. Clin Immunol. 2005;115:93–101. doi:10.1016/j.clim.2004.12.002.
Le Jan S, Amy C, Cazes A, Monnot C, Lamande N, Favier J, et al. Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. Am J Pathol. 2003;162:1521–8.
Galaup A, Cazes A, Le Jan S, Philippe J, Connault E, Le Coz E, et al. Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness. Proc Natl Acad Sci USA. 2006;103:18721–6. doi:10.1073/pnas.0609025103.
Nikolopoulos SN, Blaikie P, Yoshioka T, Guo W, Giancotti FG. Integrin beta4 signaling promotes tumor angiogenesis. Cancer Cell. 2004;6:471–83. doi:10.1016/j.ccr.2004.09.029.
van Hinsbergh VW, Engelse MA, Quax PH. Pericellular proteases in angiogenesis and vasculogenesis. Arterioscler Thromb Vasc Biol. 2006;26:716–28. doi:10.1161/01.ATV.0000209518.58252.17.
NicAmhlaoibh R, Shtivelman E. Metastasis suppressor CC3 inhibits angiogenic properties of tumor cells in vitro. Oncogene. 2001;20:270–5. doi:10.1038/sj.onc.1204075.
Hayrabedyan S, Kyurkchiev S, Kehayov I. FGF-1 and S100A13 possibly contribute to angiogenesis in endometriosis. J Reprod Immunol. 2005;67:87–101. doi:10.1016/j.jri.2005.07.001.
Iizuka M, Abe M, Shiiba K, Sasaki I, Sato Y. Down syndrome candidate region 1, a downstream target of VEGF, participates in endothelial cell migration and angiogenesis. J Vasc Res. 2004;41:334–44. doi:10.1159/000079832.
Stein T, Salomonis N, Gusterson BA. Mammary gland involution as a multi-step process. J Mammary Gland Biol Neoplasia. 2007;12:25–35. doi:10.1007/s10911-007-9035-7.
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–45. doi:10.1016/S0140-6736(00)04046-0.
Blanchard A, Shiu R, Booth S, Sorensen G, DeCorby N, Nistor A, et al. Gene expression profiling of early involuting mammary gland reveals novel genes potentially relevant to human breast cancer. Front Biosci. 2007;12:2221–32. doi:10.2741/2225.
Nuyten DS, Kreike B, Hart AA, Chi JT, Sneddon JB, Wessels LF, et al. Predicting a local recurrence after breast-conserving therapy by gene expression profiling. Breast Cancer Res. 2006;8:R62. doi:10.1186/bcr1614.
Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004;4:349–60. doi:10.1038/nrc1361.
Orlowski RZ, Dees EC. The role of the ubiquitination-proteasome pathway in breast cancer: applying drugs that affect the ubiquitin-proteasome pathway to the therapy of breast cancer. Breast Cancer Res. 2003;5:1–7. doi:10.1186/bcr460.
Daniel KG, Chen D, Yan B, Dou QP. Copper-binding compounds as proteasome inhibitors and apoptosis inducers in human cancer. Front Biosci. 2007;12:135–44. doi:10.2741/2054.
Daniel KG, Kuhn DJ, Kazi A, Dou QP. Anti-angiogenic and anti-tumor properties of proteasome inhibitors. Curr Cancer Drug Targets. 2005;5:529–41. doi:10.2174/156800905774574075.
Monks J, Geske FJ, Lehman L, Fadok VA. Do inflammatory cells participate in mammary gland involution? J Mammary Gland Biol Neoplasia. 2002;7:163–76. doi:10.1023/A:1020351919634.
Monks J, Smith-Steinhart C, Kruk ER, Fadok VA, Henson PM. Epithelial cells remove apoptotic epithelial cells during post-lactation involution of the mouse mammary gland. Biol Reprod. 2008;78:586–94. doi:10.1095/biolreprod.107.065045.
Kelleher SL, Lonnerdal B. Mammary gland copper transport is stimulated by prolactin through alterations in Ctr1 and Atp7A localization. Am J Physiol Regul Integr Comp Physiol. 2006;291:R1181–91. doi:10.1152/ajpregu.00206.2005.
Keen CL, Lonnerdal B, Clegg M, Hurley LS. Developmental changes in composition of rat milk: trace elements, minerals, protein, carbohydrate and fat. J Nutr. 1981;111:226–36.
Cerveza PJ, Mehrbod F, Cotton SJ, Lomeli N, Linder MC, Fonda EG, et al. Milk ceruloplasmin and its expression by mammary gland and liver in pigs. Arch Biochem Biophys. 2000;373:451–61. doi:10.1006/abbi.1999.1572.
Donley SA, Ilagan BJ, Rim H, Linder MC. Copper transport to mammary gland and milk during lactation in rats. Am J Physiol Endocrinol Metab. 2002;283:E667–75.
Linder MC, Wooten L, Cerveza P, Cotton S, Shulze R, Lomeli N. Copper transport. Am J Clin Nutr. 1998;67:965S–71S.
Jaeger JL, Shimizu N, Gitlin JD. Tissue-specific ceruloplasmin gene expression in the mammary gland. Biochem J. 1991;280(Pt 3):671–7.
Michalczyk A, Bastow E, Greenough M, Camakaris J, Freestone D, Taylor P, et al. ATP7B expression in human breast epithelial cells is mediated by lactational hormones. J Histochem Cytochem. 2008;56:389–99. doi:10.1369/jhc.7A7300.2008.
Llanos RM, Michalczyk AA, Freestone DJ, Currie S, Linder MC, Ackland ML, et al. Copper transport during lactation in transgenic mice expressing the human ATP7A protein. Biochem Biophys Res Commun. 2008;372:613–7. doi:10.1016/j.bbrc.2008.05.123.
Hamza I, Prohaska J, Gitlin JD. Essential role for Atox1 in the copper-mediated intracellular trafficking of the Menkes ATPase. Proc Natl Acad Sci USA. 2003;100:1215–20. doi:10.1073/pnas.0336230100.
Hamza I, Faisst A, Prohaska J, Chen J, Gruss P, Gitlin JD. The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proc Natl Acad Sci USA. 2001;98:6848–52. doi:10.1073/pnas.111058498.
Linder MC. Copper and genomic stability in mammals. Mutat Res. 2001;475:141–52. doi:10.1016/S0027-5107(01)00076-8.
Goldstein IM, Kaplan HB, Edelson HS, Weissmann G. A new function for ceruloplasmin as an acute-phase reactant in inflammation: a scavenger of superoxide anion radicals. Trans Assoc Am Physicians. 1979;92:360–9.
Goldstein IM, Kaplan HB, Edelson HS, Weissmann G. Ceruloplasmin: an acute phase reactant that scavenges oxygen-derived free radicals. Ann N Y Acad Sci. 1982;389:368–79. doi:10.1111/j.1749-6632.1982.tb22150.x.
Geraki K, Farquharson MJ, Bradley DA. Concentrations of Fe, Cu and Zn in breast tissue: a synchrotron XRF study. Phys Med Biol. 2002;47:2327–39. doi:10.1088/0031-9155/47/13/310.
Geraki K, Farquharson MJ, Bradley DA. X-ray fluorescence and energy dispersive x-ray diffraction for the quantification of elemental concentrations in breast tissue. Phys Med Biol. 2004;49:99–110. doi:10.1088/0031-9155/49/1/007.
Gupte A, Mumper RJ. Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treat Rev. 2009;35:32–46. doi:10.1016/j.ctrv.2008.07.004.
Lowndes SA, Harris AL. The role of copper in tumour angiogenesis. J Mammary Gland Biol Neoplasia. 2005;10:299–310. doi:10.1007/s10911-006-9003-7.
Gupta SK, Shukla VK, Vaidya MP, Roy SK, Gupta S. Serum trace elements and Cu/Zn ratio in breast cancer patients. J Surg Oncol. 1991;46:178–81. doi:10.1002/jso.2930460311.
Safaei R. Role of copper transporters in the uptake and efflux of platinum containing drugs. Cancer Lett. 2006;234:34–9. doi:10.1016/j.canlet.2005.07.046.
Pan Q, Kleer CG, van Golen KL, Irani J, Bottema KM, Bias C, et al. Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis. Cancer Res. 2002;62:4854–9.
Brewer GJ. Copper lowering therapy with tetrathiomolybdate as an antiangiogenic strategy in cancer. Curr Cancer Drug Targets. 2005;5:195–202. doi:10.2174/1568009053765807.
Hough CD, Cho KR, Zonderman AB, Schwartz DR, Morin PJ. Coordinately up-regulated genes in ovarian cancer. Cancer Res. 2001;61:3869–76.
Stassar MJ, Devitt G, Brosius M, Rinnab L, Prang J, Schradin T, et al. Identification of human renal cell carcinoma associated genes by suppression subtractive hybridization. Br J Cancer. 2001;85:1372–82. doi:10.1054/bjoc.2001.2074.
Song B. Immunohistochemical demonstration of epidermal growth factor receptor and ceruloplasmin in thyroid diseases. Acta Pathol Jpn. 1991;41:336–43.
Tuccari G, Barresi G. Immunohistochemical demonstration of ceruloplasmin in follicular adenomas and thyroid carcinomas. Histopathology. 1987;11:723–31. doi:10.1111/j.1365-2559.1987.tb02686.x.
Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, Carey LA, Reynolds E, Dressler L, et al. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics. 2006;7:96. doi:10.1186/1471-2164-7-96
Schapira DV, Schapira M. Use of ceruloplasmin levels to monitor response to therapy and predict recurrence of breast cancer. Breast Cancer Res Treat. 1983;3:221–4. doi:10.1007/BF01803564.
Martin F, Linden T, Katschinski DM, Oehme F, Flamme I, Mukhopadhyay CK, et al. Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation. Blood. 2005;105:4613–9. doi:10.1182/blood-2004-10-3980.
Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436:518–24. doi:10.1038/nature03799.
Albini A, Sporn MB. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer. 2007;7:139–47. doi:10.1038/nrc2067.
Yoshii J, Yoshiji H, Kuriyama S, Ikenaka Y, Noguchi R, Okuda H, et al. The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells. Int J Cancer. 2001;94:768–73. doi:10.1002/ijc.1537.
Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Yanase K, et al. The copper-chelating agent, trientine, attenuates liver enzyme-altered preneoplastic lesions in rats by angiogenesis suppression. Oncol Rep. 2003;10:1369–73.
Yoshiji H, Yoshii J, Kuriyama S, Ikenaka Y, Noguchi R, Yanase K, et al. Combination of copper-chelating agent, trientine, and methotrexate attenuates colorectal carcinoma development and angiogenesis in mice. Oncol Rep. 2005;14:213–8.
Das D, Tapryal N, Goswami SK, Fox PL, Mukhopadhyay CK. Regulation of ceruloplasmin in human hepatic cells by redox active copper: identification of a novel AP-1 site in the ceruloplasmin gene. Biochem J. 2007;402:135–41. doi:10.1042/BJ20060963.
Liao D, Corle C, Seagroves TN, Johnson RS. Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res. 2007;67:563–72. doi:10.1158/0008-5472.CAN-06-2701.
Dales JP, Garcia S, Meunier-Carpentier S, Andrac-Meyer L, Haddad O, Lavaut MN, et al. Overexpression of hypoxia-inducible factor HIF-1alpha predicts early relapse in breast cancer: retrospective study in a series of 745 patients. Int J Cancer. 2005;116:734–9. doi:10.1002/ijc.20984.
Zheng X, Ruas JL, Cao R, Salomons FA, Cao Y, Poellinger L, et al. Cell-type-specific regulation of degradation of hypoxia-inducible factor 1 alpha: role of subcellular compartmentalization. Mol Cell Biol. 2006;26:4628–41. doi:10.1128/MCB.02236-05.
Okada K, Osaki M, Araki K, Ishiguro K, Ito H, Ohgi S. Expression of hypoxia-inducible factor (HIF-1alpha), VEGF-C and VEGF-D in non-invasive and invasive breast ductal carcinomas. Anticancer Res. 2005;25:3003–9.
Seagroves TN, Hadsell D, McManaman J, Palmer C, Liao D, McNulty W, et al. HIF1alpha is a critical regulator of secretory differentiation and activation, but not vascular expansion, in the mouse mammary gland. Development. 2003;130:1713–24. doi:10.1242/dev.00403.
Kim I, Kim HG, Kim H, Kim HH, Park SK, Uhm CS, et al. Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis. Biochem J. 2000;346(Pt 3):603–10. doi:10.1042/0264-6021:3460603.
Anderson SM, Rudolph MC, McManaman JL, Neville MC. Key stages in mammary gland development. Secretory activation in the mammary gland: it's not just about milk protein synthesis! Breast Cancer Res. 2007;9:204. doi:10.1186/bcr1653
Rudolph MC, McManaman JL, Phang T, Russell T, Kominsky DJ, Serkova NJ, et al. Metabolic regulation in the lactating mammary gland: a lipid synthesizing machine. Physiol Genomics. 2007;28:323–36. doi:10.1152/physiolgenomics.00020.2006.
Rudolph MC, Neville MC, Anderson SM. Lipid synthesis in lactation: diet and the fatty acid switch. J Mammary Gland Biol Neoplasia. 2007;12:269–81. doi:10.1007/s10911-007-9061-5.
Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7:763–77. doi:10.1038/nrc2222.
Ning Y, Hoang B, Schuller AG, Cominski TP, Hsu MS, Wood TL, et al. Delayed mammary gland involution in mice with mutation of the insulin-like growth factor binding protein 5 gene. Endocrinology. 2007;148:2138–47. doi:10.1210/en.2006-0041.
Tonner E, Barber MC, Allan GJ, Beattie J, Webster J, Whitelaw CB, et al. Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice. Development. 2002;129:4547–57.
Flint DJ, Boutinaud M, Tonner E, Wilde CJ, Hurley W, Accorsi PA, et al. Insulin-like growth factor binding proteins initiate cell death and extracellular matrix remodeling in the mammary gland. Domest Anim Endocrinol. 2005;29:274–82. doi:10.1016/j.domaniend.2005.02.021.
Kricker JA, Towne CL, Firth SM, Herington AC, Upton Z. Structural and functional evidence for the interaction of insulin-like growth factors (IGFs) and IGF binding proteins with vitronectin. Endocrinology. 2003;144:2807–15. doi:10.1210/en.2002-221086.
Akkiprik M, Feng Y, Wang H, Chen K, Hu L, Sahin A, et al. Multifunctional roles of insulin-like growth factor binding protein 5 in breast cancer. Breast Cancer Res. 2008;10:212. doi:10.1186/bcr2116.
Li X, Cao X, Li X, Zhang W, Feng Y. Expression level of insulin-like growth factor binding protein 5 mRNA is a prognostic factor for breast cancer. Cancer Sci. 2007;98:1592–6. doi:10.1111/j.1349-7006.2007.00565.x.
Mita K, Zhang Z, Ando Y, Toyama T, Hamaguchi M, Kobayashi S, et al. Prognostic significance of insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 expression in breast cancer. Jpn J Clin Oncol. 2007;37:575–82. doi:10.1093/jjco/hym066.
Wang H, Arun BK, Wang H, Fuller GN, Zhang W, Middleton LP, et al. IGFBP2 and IGFBP5 overexpression correlates with the lymph node metastasis in T1 breast carcinomas. Breast J. 2008;14:261–7. doi:10.1111/j.1524-4741.2008.00572.x.
Hao X, Sun B, Hu L, Lahdesmaki H, Dunmire V, Feng Y, et al. Differential gene and protein expression in primary breast malignancies and their lymph node metastases as revealed by combined cDNA microarray and tissue microarray analysis. Cancer. 2004;100:1110–22. doi:10.1002/cncr.20095.
Condeelis J, Singer RH, Segall JE. The great escape: when cancer cells hijack the genes for chemotaxis and motility. Annu Rev Cell Dev Biol. 2005;21:695–718. doi:10.1146/annurev.cellbio.21.122303.120306.
Wang W, Wyckoff JB, Wang Y, Bottinger EP, Segall JE, Condeelis JS. Gene expression analysis on small numbers of invasive cells collected by chemotaxis from primary mammary tumors of the mouse. BMC Biotechnol. 2003;3:13. doi:10.1186/1472-6750-3-13.
Hewitt KJ, Agarwal R, Morin PJ. The claudin gene family: expression in normal and neoplastic tissues. BMC Cancer. 2006;6:186. doi:10.1186/1471-2407-6-186.
Yamaguchi H, Lorenz M, Kempiak S, Sarmiento C, Coniglio S, Symons M, et al. Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin. J Cell Biol. 2005;168:441–52. doi:10.1083/jcb.200407076.
Agarwal R, D'Souza T, Morin PJ. Claudin-3 and claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity. Cancer Res. 2005;65:7378–85. doi:10.1158/0008-5472.CAN-05-1036.
Huang YH, Bao Y, Peng W, Goldberg M, Love K, Bumcrot DA, et al. Claudin-3 gene silencing with siRNA suppresses ovarian tumor growth and metastasis. Proc Natl Acad Sci USA. 2009;106:3426–30. doi:10.1073/pnas.0813348106.
Carraway KL 3rd, Sweeney C. Co-opted integrin signaling in ErbB2-induced mammary tumor progression. Cancer Cell. 2006;10:93–5. doi:10.1016/j.ccr.2006.07.015.
Honda K, Yamada T, Endo R, Ino Y, Gotoh M, Tsuda H, et al. Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion. J Cell Biol. 1998;140:1383–93. doi:10.1083/jcb.140.6.1383.
Otey CA, Pavalko FM, Burridge K. An interaction between alpha-actinin and the beta 1 integrin subunit in vitro. J Cell Biol. 1990;111:721–9. doi:10.1083/jcb.111.2.721.
Burridge K, Nuckolls G, Otey C, Pavalko F, Simon K, Turner C. Actin-membrane interaction in focal adhesions. Cell Differ Dev. 1990;32:337–42. doi:10.1016/0922-3371(90)90048-2.
Dudoit S, Gentleman RC, Quackenbush J. Open source software for the analysis of microarray data. Biotechniques. 2003;(Suppl):45–51.
Wu Z, Irizarry RA, Gentleman R, Martinez-Murillo F, Spencer F. A Model-Based Background Adjustment for Oligonucleotide Expression Arrays. J Am Stat Assoc. 2004;99:909–17. doi:10.1198/016214504000000683.
Nuyten DS, Hastie T, Chi JT, Chang HY, van de Vijver MJ. Combining biological gene expression signatures in predicting outcome in breast cancer: An alternative to supervised classification. Eur J Cancer. 2008;44:2319–29. doi:10.1016/j.ejca.2008.07.015.
Wheeler DL, Barrett T, Benson DA, Bryant SH, Canese K, Chetvernin V, et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 2006;34:D173–80. doi:10.1093/nar/gkj158.
Acknowledgements
The authors would like to thank Drs David Flint and Pepper Schedin for very helpful discussions, and Dr Jennifer Richer for very valuable feedback. This work was funded by Breakthrough Breast Cancer through a programme grant to B. Gusterson, and the Dutch Cancer Society Grant NKB 2002–2575 to D.S.A. Nuyten and M.J. van de Vijver.
The complete datasets are available at http://conklinwolf.ucsf.edu/informatics/oncosplit.html.
Competing Interest
No competing interest declared.
Author information
Authors and Affiliations
Corresponding author
Additional information
An erratum to this article can be found at http://dx.doi.org/10.1007/s10911-009-9127-7
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Stein, T., Salomonis, N., Nuyten, D.S.A. et al. A Mouse Mammary Gland Involution mRNA Signature Identifies Biological Pathways Potentially Associated with Breast Cancer Metastasis. J Mammary Gland Biol Neoplasia 14, 99–116 (2009). https://doi.org/10.1007/s10911-009-9120-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10911-009-9120-1