Abstract
Secreted proteins of the Wnt family play widespread roles in the regulation of embryonic development, and aberrant activation of the canonical Wnt/β-catenin pathway is one of the most frequent signaling abnormalities known in human cancer. While the consequences of Wnt signaling in development are diverse at the cellular level, they are often concerned with cell fate determination. Recent data also indicate that Wnt proteins influence the self-renewal of stem cells in certain tissues. In the mammary gland, Wnt signals are strongly implicated in initial development of the mammary rudiments, and in the ductal branching and alveolar morphogenesis that occurs during pregnancy. Transgenic expression of Wnt1 or Wnt10b in the mouse mammary gland leads to lobuloalveolar hyperplasia with a major risk of progression to carcinoma. Recent evidence suggests that this phenotype is associated with expansion of a multipotent progenitor cell population. In human breast cancer, evidence of β-catenin accumulation implies that the canonical Wnt signaling pathway is active in over 50% of carcinomas. However, specific mutations that might account for this activation of signaling have not yet been identified.
Similar content being viewed by others
REFERENCES
Rijsewijk F, Schuerman M, Wagenaar E, Parren P, Weigel D, Nusse R. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell 1987;50:649-657.
Nusse R, Varmus HE. Wnt genes. Cell 1992;69:1073-1087.
Miller JR. The Wnts. Genome Biol 2002;3(1):reviews 3001.1-3001.15.
Cadigan KM, Nusse R. Wnt signaling: a common theme in animal development. Genes Dev. 1997;11:3286-3305.
Polakis P. Wnt signaling and cancer. Genes Dev 2000;14(15):1837-51.
Huelsken J, Birchmeier W. New aspects of Wnt signaling pathways in higher vertebrates. Curr Opin Genet Dev 2001;11(5):547-53.
Strutt D.Frizzled signalling and cell polarisation in Drosophila and vertebrates. Development 2003;130(19):4501-13.
Veeman MT, Axelrod JD, Moon RT. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell 2003;5(3):367-77.
Kuhl M, Sheldahl LC, Park M, Miller JR, Moon RT. The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet 2000;16(7):279-83.
Yamanaka H, Moriguchi T, Masuyama N, Kusakabe M, Hanafusa H, Takada R, et al. JNK functions in the noncanonical Wnt pathway to regulate convergent extension movements in vertebrates. EMBO Rep 2002;3(1):69-75.
Strutt D, Johnson R, Cooper K, Bray S. Asymmetric localization of frizzled and the determination of notch-dependent cell fate in the Drosophila eye. Curr Biol 2002;12:813-824.
Sheldahl LC, Slusarski DC, Pandur P, Miller JR, Kuhl M, Moon RT. Dishevelled activates Ca2+ flux, PKC, and CamKII in vertebrate embryos. J Cell Biol 2003;161(4):769-77.
Payre F, Vincent A, Carreno S. ovo/svb integrates Wingless and DER pathways to control epidermis differentiation. Nature 1999;400(6741):271-5.
Kim J, Sebring A, Esch JJ, Kraus ME, Vorwerk K, Magee J, et al. Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene. Nature 1996;382(6587):133-8.
Klein T, Martinez Arias A. Different spatial and temporal interactions between Notch, wingless and vestigial specify proximal and distal elements of the wing in Drosophila. Developmental Biology 1998;194:196-212.
Dubois L, Lecourtois M, Alexandre C, Hirst E, Vincent JP. Regulated endocytic routing modulates wingless signaling in Drosophila embryos. Cell 2001;105(5):613-24.
Strigini M, Cohen SM. Wingless gradient formation in the Drosophila wing. Curr Biol 2000;10(6):293-300.
Neumann C, Cohen S. Morphogens and pattern formation. Bioessays 1997;19(8):721-9.
Martinez Arias A. Wnts as morphogens? The view from the wing of Drosophila. Nat Rev Mol Cell Biol 2003;4(4):321-5.
Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Ann Rev Cell Dev Biol 1998;14:59-88.
Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, et al. Inhibition of adipogenesis by Wnt signaling. Science 2000;289(5481):950-3.
Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW, et al. Regulation of Wnt signaling during adipogenesis. J Biol Chem 2002;277(34):30998-11004.
Cossu G, Borello U. Wnt signaling and the activation of myogenesis in mammals. Embo J 1999;18(24):6867-72.
Petropoulos H, Skerjanc IS. Beta-catenin is essential and sufficient for skeletal myogenesis in P19 cells. J Biol Chem 2002;277(18):15393-9.
Pandur P, Lasche M, Eisenberg LM, Kuhl M. Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis. Nature 2002;418(6898):636-41.
Nakamura T, Sano M, Songyang Z, Schneider MD. A Wntand beta-catenin-dependent pathway for mammalian cardiac myogenesis. Proc Natl Acad Sci U S A 2003;100(10):5834-9.
Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 2003;423(6938):448-52.
Reya T. Regulation of hematopoietic stem cell self-renewal. Recent Prog Horm Res 2003;58:283-95.
Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 2004;10(1):55-63.
Kubo F, Takeichi M, Nakagawa S. Wnt2b controls retinal cell differentiation at the ciliary marginal zone. Development 2003;130(3):587-98.
Zhu AJ, Watt FM. beta-catenin signalling modulates proliferative potential of human epidermal keratinocytes independently of intracellular adhesion. Development 1999;126:2285-98.
Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci U S A 2003;100(26):15853-8.
Liu BY, McDermott SP, Khwaja SS, Alexander CM. The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. Proc Natl Acad Sci U S A 2004;101(12):4158-63.
Lako M, Lindsay S, Lincoln J, Cairns PM, Armstrong L, Hole N. Characterisation of Wnt gene expression during the differentiation of murine embryonic stem cells in vitro: role of Wnt3 in enhancing haematopoietic differentiation. Mech Dev 2001;103(1-2):49-59.
Lee HY, Kleber M, Hari L, Brault V, Suter U, Taketo MM, et al. Instructive role of Wnt/beta-catenin in sensory fate specification in neural crest stem cells. Science 2004;303(5660):1020-3.
Noordermeer J, Klingensmith J, PerrimonN, Nusse R. dishevelled and armadillo act in the wingless signalling pathway in Drosophila. Nature 1994;367(6458):80-3.
Nusse R, Samos CH, Brink M, Willert K, Cadigan KM, Wodarz A, et al. Cell culture and whole animal approaches to understanding signaling by Wnt proteins in Drosophila. Cold Spring Harb Symp Quant Biol 1997;62:185-90.
Lawrence PA, Casal J, Struhl G. Towards a model of the organisation of planar polarity and pattern in the Drosophila abdomen. Development 2002;129(11):2749-60.
Mlodzik M. Planar cell polarization: do the same mechanisms regulate Drosophila tissue polarity and vertebrate gastrulation? Trends Genet 2002;18(11):564-71.
Heisenberg CP, Tada M, Rauch GJ, Saude L, Concha ML, Geisler R, et al. Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature 2000;405(6782):76-81.
Kilian B, Mansukoski H, Barbosa FC, Ulrich F, Tada M, Heisenberg CP. The role of Ppt/Wnt5 in regulating cell shape and movement during zebrafish gastrulation. Mech Dev 2003;120(4):467-76.
Copp AJ, Greene ND, Murdoch JN. Dishevelled: linking convergent extension with neural tube closure. Trends Neurosci 2003;26(9):453-5.
Curtin JA, Quint E, Tsipouri V, Arkell RM, Cattanach B, Copp AJ, et al. Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr Biol 2003;13(13):1129-33.
Montcouquiol M, Rachel RA, Lanford PJ, Copeland NG, Jenkins NA, Kelley MW. Identification ofVangl2 and Scrb1 as planar polarity genes inmammals. Nature 2003;423(6936):173-7.
Park FD, Priess JR. Establishment of POP-1 asymmetry in early C. elegans embryos. Development 2003;130(15):3547-56.
Korswagen HC. Canonical and non-canonical Wnt signaling pathways in Caenorhabditis elegans: variations on a common signaling theme. Bioessays 2002;24(9):801-10.
Schlesinger A, Shelton CA, Maloof JN, Meneghini M, Bowerman B. Wnt pathway components orient a mitotic spindle in the early Caenorhabditis elegans embryo without requiring gene transcription in the responding cell. Genes Dev 1999;13(15):2028-38.
Lu B, Roegiers F, Jan LY, Jan YN. Adherens junctions inhibit asymmetric division in the Drosophila epithelium. Nature 2001;409(6819):522-5.
Yamashita YM, Jones DL, Fuller MT. Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 2003;301(5639):1547-50.
Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ, et al. Depletion of epithelial stem-cell 130 Brennan and Brown compartments in the small intestine of mice lacking Tcf-4. Nat Genet 1998;19(4):379-83.
Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003;423(6938):409-14.
Howe LR, Brown AM. Wnt Signaling and Breast Cancer. Cancer Biol Ther 2004;3(1).
Hatsell S, Rowlands T, Hiremath M, Cowin P. Beta-catenin and Tcfs in mammary development and cancer. J Mammary Gland Biol Neoplasia 2003;8(2):145-58.
Smalley MJ, Dale TC. Wnt signaling and mammary tumorigenesis. J Mammary Gland Biol Neoplasia 2001;6(1):37-52.
Lacher MD, Siegenthaler A, Jager R, Yan X, Hett S, Xuan L, et al. Role of DDC-4/sFRP-4, a secreted frizzled-related protein, at the onset of apoptosis in mammary involution. Cell Death Differ 2003;10(5):528-38.
Cunha GR, Hom YK, Young P, Brody J. Transplantation and tissue recombination techniques to study mammary gland biology. In: Ip MM, Asch BB, editors. Methods in Mammary Gland Biology and Breast Cancer Research. New York: Kluwer Academic / Plenum; 2000. p. 289-306.
van Genderen C, Okamura RM, Farinas I, Quo RG, Parslow TG, Bruhn L, et al. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev 1994;8(22):2691-703.
Foley J, Dann P, Hong J, Cosgrove J, Dreyer B, Rimm D, et al. Parathyroid hormone-related protein maintains mammary epithelial fate and triggers nipple skin differentiation during embryonic breast development. Development 2001;128(4):513-25.
DasGupta R, Fuchs E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 1999;126(20):4557-68.
Christiansen JH, Dennis CL, Wicking CA, Monkley SJ, Wilkinson DG, Wainwright BJ. Murine Wnt-11 and Wnt-12 have temporally and spatially restricted expression patterns during embryonic development. Mech Dev 1995;51(2-3):341-50.
Andl T, Reddy ST, Gaddapara T, Millar SE. WNT signals are required for the initiation of hair follicle development. Dev Cell 2002;2(5):643-53.
Bafico A, LiuG, Yaniv A, Gazit A, Aaronson SA. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol 2001;3(7): 683-6.
MaoB, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, et al. LDLreceptor-related protein 6 is a receptor for Dickkopf proteins. Nature 2001;411(6835):321-5.
Willert J, Epping M, Pollack JR, Brown PO, Nusse R. A transcriptional response to Wnt protein in human embryonic carcinoma cells. BMC Dev Biol 2002;2(1):8.
Phippard DJ, Weber-Hall SJ, Sharpe PT, Naylor MS, Jayatalake H, Maas R, et al. Regulation of Msx-1, Msx-2,Bmp-2 and Bmp-4 during foetal and postnatal mammary gland development. Development 1996;122(9):2729-37.
Satokata I, Ma L, Ohshima H, Bei M, Woo I, Nishizawa K, et al. Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat Genet 2000;24(4):391-5.
Daniel CW, Silberstein GB. Postnatal development of the rodent mammary gland. In: Neville MC, Daniel CW, editors. The Mammary Gland. New York: Plenum Press; 1987. p. 3-36.
Smalley M, Ashworth A. Stem cells and breast cancer:Afield in transit. Nat Rev Cancer 2003;3(11):832-44.
Bergstein I, Brown AMC. WNT genes and breast cancer. In: Bowcock AM, editor. Breast Cancer: Molecular Genetics, Pathogenesis and Therapeutics: Humana Press Inc.; 1999. p. 181-98.
Lane TF, Leder P. Wnt-10b directs hypermorphic development and transformation in mammary glands of male and female mice. Oncogene 1997;15:2133-2144.
Buhler TA, Dale TC, Kieback C, Humphreys RC, Rosen JM. Localization and quantification of Wnt-2 gene expression in mouse mammary development. Devl.Biol. 1993;155:87-96.
Lin TP, Guzman RC, Osborn RC, Thordarson G, Nandi S. Role of endocrine, autocrine, and paracrine interactions in the development of mammary hyperplasia in Wnt-1 transgenic mice. Cancer Res. 1992;52:413-419.
Tsukamoto AS, Grosschedl R, Guzman RC, Parslow T, Varmus HE. Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 1988;55:619-625.
Bocchinfuso WP, Hively WP, Couse JF, Varmus HE, Korach KS. A mouse mammary tumor virus-Wnt-1 transgene induces mammary gland hyperplasia and tumorigenesis in mice lacking estrogen receptor-alpha. Cancer Res 1999;59(8): 1869-76.
Gallagher RC, Hay T, Meniel V, Naughton C, Anderson TJ, Shibata H, et al. Inactivation of Apc perturbs mammary development, but only directly results in acanthoma in the context of Tcf-1 deficiency. Oncogene 2002;21(42):6446-57.
Weeraratna AT, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, et al. Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell 2002;1(3):279-88.
Gavin BJ, McMahon AP. Differential regulation of the Wnt gene family during pregnancy and lactation suggests a role in postnatal development of the mammary gland. Mol. Cell. Biol. 1992;12:2418-2423.
Weber-Hall SJ, Phippard DJ, Niemeyer CC, Dale TC. Developmental and hormonal regulation of Wnt gene expression in the mouse mammary gland. Differentiation 1994;57(3): 205-14.
Bradbury JM, Edwards PAW, Niemeyer CC, Dale TC. Wnt-4 expression induces a pregnancy-like growth pattern in reconstructed mammary glands in virgin mice. Devl. Biol. 1995;170:553-563.
Brisken C, Heineman A, Chavarria T, Elenbaas B, Tan J, Dey SK, et al. Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes Dev 2000;14(6):650-4.
Shimizu H, Julius MA, Zheng Z, Giarre M, Brown AMC, Kitajewski J. Mammary cell transformation by Wnt family proteins correlates with regulation of beta-catenin. Cell growth and differentiation 1997;8:1349-1358.
Uyttendaele H, Soriano JV, Montesano R, Kitajewski J. Notch4 and Wnt-1 proteins function to regulate branching morphogenesis of mammary epithelial cells in an opposing fashion. Dev Biol 1998;196(2):204-17.
Miyoshi K, Shillingford JM, Le Provost F, Gounari F, Bronson R, von Boehmer H, et al. Activation of beta-catenin signaling in differentiated mammary secretory cells induces transdifferentiation into epidermis and squamous metaplasias. Proc Natl Acad Sci U S A 2002;99(1):219-24.
Imbert A, Eelkema R, Jordan S, Feiner H, Cowin P. Delta-N89beta-catenin induces precocious development, differentiation, and neoplasia in mammary gland. J Cell Biol 2001:in press.
Michaelson JS, Leder P. beta-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland. Oncogene 2001;20(37):5093-9.
Hsu W, Shakya R, Costantini F. Impaired mammary gland and lymphoid development caused by inducible expression of Axin in transgenic mice. J Cell Biol 2001;155(6):1055-64.
Tepera SB, McCrea PD, Rosen JM. A beta-catenin survival signal is required for normal lobular development in the mammary gland. J Cell Sci 2003;116(Pt 6):1137-49.
Martinez Arias A, Brown AMC, Brennan K. Wnt signalling: pathway or network? Curr Opin Genet Dev 1999;9(4):447-54.
Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982;31:99-109.
LiY, Hively WP, Varmus HE.Use ofMMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer. Oncogene 2000;19(8):1002-9.
Moser AR, Mattes EM, Dove WF, Lindstrom MJ, Haag JD, Gould MN. ApcMin, a mutation in the murine Apc gene, predisposes to mammary carcinomas and focal alveolar hyperplasias. Proc Natl Acad Sci U S A 1993;90(19):8977-81.
Gunther EJ, Moody SE, Belka GK, Hahn KT, Innocent N, Dugan KD, et al. Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. Genes Dev 2003;17(4):488-501.
Sell S, Pierce GB. Maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial cancers. Lab Invest 1994;70(1):6-22.
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414(6859): 105-11.
Brown AMC. Wnt signaling in breast cancer: have we come full circle? Breast Cancer Res 2001;3(6):351-5.
Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, et al. Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci U S A 2000;97(8):4262-6.
Ryo A, Nakamura M, Wulf G, Liou YC, Lu KP. Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC. Nat Cell Biol 2001;3(9):793-801.
Ugolini F, Charafe-Jauffret E, Bardou VJ, Geneix J, Adelaide J, Labat-Moleur F, et al.WNT pathway andmammarycarcinogenesis: loss of expression of candidate tumor suppressor gene SFRP1 in most invasive carcinomas except of the medullary type. Oncogene 2001;20(41):5810-7.
Wissmann C, Wild PJ, Kaiser S, Roepcke S, Stoehr R, Woenckhaus M, et al. WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer. J Pathol 2003;201(2):204-12.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003;100(7): 3983-8.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Brennan, K.R., Brown, A.M.C. Wnt Proteins in Mammary Development and Cancer. J Mammary Gland Biol Neoplasia 9, 119–131 (2004). https://doi.org/10.1023/B:JOMG.0000037157.94207.33
Issue Date:
DOI: https://doi.org/10.1023/B:JOMG.0000037157.94207.33