Skip to main content

Advertisement

SpringerLink
Log in

Transforming Growth Factor-βs and Mammary Gland Involution; Functional Roles and Implications for Cancer Progression

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

During rodent mammary gland involution there is a dramatic increase in the expression of the transforming growth factor-β isoform, TGF-β3. The TGF-βs are multifunctional cytokines which play important roles in wound healing and in carcinogenesis. The responses that are activated in the remodeling of the gland during involution have many similarities with the wound healing process and have been postulated to generate a mammary stroma that provides a microenvironment favoring tumor progression. In this review we will discuss the putative role of TGF-β during involution, as well as its effects on the mammary microenvironment and possible implications for pregnancy-associated tumorigenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Abbreviations

ADAM:

A disintigrin and metallopeptidase domain

BMP:

bone morphogenetic protein

CTGF:

connective tissue growth factor

DNIIR:

dominant-negative TGF-β type II receptor

ECM:

extracellular matrix

MAPK:

mitogen-activated protein kinase

MEC:

mammary epithelial cells

MMP:

matrix metalloproteinases

MMTV:

mouse mammary tumor virus

PI-3:

Phosphatidylinostitol-3

SPARC:

secreted acidic cysteine rich glycoprotein

TβRI:

TGF-β type I receptor

TβRII:

TGF-β type II receptor

TGF-β:

transforming growth factor-β

Tsc-22:

TGF-β-stimulated clone 22

References

  1. 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.

    Article  PubMed  Google Scholar 

  2. Strange R, Li F, Saurer S, Burkhardt A, Friis RR. Apoptotic cell death and tissue remodelling during mouse mammary gland involution. Development. 1992;115:49–58.

    PubMed  CAS  Google Scholar 

  3. Lund LR, Romer J, Thomasset N, Solberg H, Pyke C, Bissell MJ, et al. Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways. Development. 1996;122:181–93.

    PubMed  CAS  Google Scholar 

  4. Schedin P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer. 2006;6:281–91.

    Article  PubMed  CAS  Google Scholar 

  5. 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.

    Article  PubMed  Google Scholar 

  6. Sieweke MH, Stoker AW, Bissell MJ. Evaluation of the cocarcinogenic effect of wounding in Rous sarcoma virus tumorigenesis. Cancer Res. 1989;49:6419–24.

    PubMed  CAS  Google Scholar 

  7. Stuelten CH, Barbul A, Busch JI, Sutton E, Katz R, Sato M, et al. Acute wounds accelerate tumorigenesis by a T cell-dependent mechanism. Cancer Res. 2008;68:7278–82.

    Article  PubMed  CAS  Google Scholar 

  8. 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 U S A. 2005;102:3738–43.

    Article  PubMed  CAS  Google Scholar 

  9. Flanders KC. Smad3 as a mediator of the fibrotic response. Int J Exp Pathol. 2004;85:47–64.

    Article  PubMed  CAS  Google Scholar 

  10. Roberts AB. Sporn, MB. Transforming growth factor-beta. In: Clark RAF, editor. The molecular and cellular biology of wound repair. New York: Plenum; 1996. p. 275–308.

    Google Scholar 

  11. Feng XH, Derynck R. Specificity and versatility in TGF-beta signaling through Smads. Annu Rev Cell Dev Biol. 2005;21:659–93.

    Article  PubMed  CAS  Google Scholar 

  12. Massague J, Gomis RR. The logic of TGFbeta signaling. FEBS Lett. 2006;580:2811–20.

    Article  PubMed  CAS  Google Scholar 

  13. Roberts AB, Sporn MB. The transforming growth factor-betas. In: Roberts AB, Sporn MB, editors. Handbook of experimental pharmacology vol. 95. New York: Springer-Verlag; 1990. p. 419–72.

    Google Scholar 

  14. Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta. 2008;1782:197–228.

    PubMed  CAS  Google Scholar 

  15. Massague J. TGF-beta in cancer. Cell. 2008;134:215–30.

    Article  PubMed  CAS  Google Scholar 

  16. Reiss M. TGF-beta and cancer. Microbes Infect. 1999;1:1327–47.

    Article  PubMed  CAS  Google Scholar 

  17. Kingsley DM. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 1994;8133–46.

  18. Jeruss JS, Santiago JY, Woodruff TK. Localization of activin and inhibin subunits, receptors and SMADs in the mouse mammary gland. Mol Cell Endocrinol. 2003;203:185–96.

    Article  PubMed  CAS  Google Scholar 

  19. Manickam R, Pena RN, Whitelaw CB. Mammary gland differentiation inversely correlates with GDF-8 expression. Mol Reprod Dev. 2008;75:1783–8.

    Article  PubMed  CAS  Google Scholar 

  20. 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;122:2729–37.

    PubMed  CAS  Google Scholar 

  21. Kulkarni AB, Thyagarajan T, Letterio JJ. Function of cytokines within the TGF-beta superfamily as determined from transgenic and gene knockout studies in mice. Curr Mol Med. 2002;2:303–27.

    Article  PubMed  CAS  Google Scholar 

  22. Pelton RW, Hogan BL, Miller DA, Moses HL. Differential expression of genes encoding TGFs beta 1, beta 2, and beta 3 during murine palate formation. Dev Biol. 1990;141:456–60.

    Article  PubMed  CAS  Google Scholar 

  23. Proetzel G, Pawlowski SA, Wiles MV, Yin M, Boivin GP, Howles PN, et al. Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet. 1995;11:409–14.

    Article  PubMed  CAS  Google Scholar 

  24. Yang LT, Kaartinen V. Tgfβ1 expressed in the Tgfβ3 locus partially rescues the cleft palate phenotype of Tgfβ3 null mutants. Dev Biol. 2007;312:384–95.

    Article  PubMed  CAS  Google Scholar 

  25. Merwin JR, Newman W, Beall LD, Tucker A, Madri J. Vascular cells respond differentially to transforming growth factors beta 1 and beta 2 in vitro. Am J Pathol. 1991;138:37–51.

    PubMed  CAS  Google Scholar 

  26. Ellis IR, Banyard J, Schor SL. Motogenic and biosynthetic response of adult skin fibroblasts to TGF-beta isoforms (−1, −2, and −3) determined by ‘tissue-response unit’: Role of cell density and substratum. Cell Biol Int. 1999;23:593–602.

    Article  PubMed  CAS  Google Scholar 

  27. Li J, Foitzik K, Calautti E, Baden H, Doetschman T, Dotto GP. TGF-beta3, but not TGF-beta1, protects keratinocytes against 12-O-tetradecanoylphorbol-13-acetate-induced cell death in vitro and in vivo. J Biol Chem. 1999;274:4213–9.

    Article  PubMed  CAS  Google Scholar 

  28. Massague J, Seoane J, Wotton D. Smad transcription factors. Genes Dev. 2005;19:2783–810.

    Article  PubMed  CAS  Google Scholar 

  29. Schmierer B, Hill CS. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol. 2007;8:970–82.

    Article  PubMed  CAS  Google Scholar 

  30. Daly AC, Randall RA, Hill CS. Transforming growth factor beta-induced Smad1/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth. Mol Cell Biol. 2008;28:6889–902.

    Article  PubMed  CAS  Google Scholar 

  31. Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke DP. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 2002;21:1743–53.

    Article  PubMed  CAS  Google Scholar 

  32. Wakefield LM, Roberts AB. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev. 2002;12:22–9.

    Article  PubMed  CAS  Google Scholar 

  33. Wrighton KH, Feng XH. To (TGF) beta or not to (TGF) beta: fine-tuning of Smad signaling via post-translational modifications. Cell Signal. 2008;20:1579–91.

    Article  PubMed  CAS  Google Scholar 

  34. Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res. 2009;19:128–39.

    Article  PubMed  CAS  Google Scholar 

  35. Eivers E, Fuentealba LC, De Robertis EM. Integrating positional information at the level of Smad1/5/8. Curr Opin Genet Dev. 2008;18:304–10.

    Article  PubMed  CAS  Google Scholar 

  36. Arrick BA, Lee AL, Grendell RL, Derynck R. Inhibition of translation of transforming growth factor-beta 3 mRNA by its 5′ untranslated region. Mol Cell Biol. 1991;11:4306–13.

    PubMed  CAS  Google Scholar 

  37. Kim SJ, Park K, Koeller D, Kim KY, Wakefield LM, Sporn MB, et al. Post-transcriptional regulation of the human transforming growth factor-beta 1 gene. J Biol Chem. 1992;267:13702–7.

    PubMed  CAS  Google Scholar 

  38. Annes J, Munger JS, Rifkin DB. Making sense of latent TGF-beta activation. J Cell Sci. 2003;116:217–224.

    Article  PubMed  CAS  Google Scholar 

  39. Wipff PJ, Hinz B. Integrins and the activation of latent transforming growth factor beta1—an intimate relationship. Eur J Cell Biol. 2008;87:601–15.

    Article  PubMed  CAS  Google Scholar 

  40. Isogai Z, Ono RN, Ushiro S, Keene DR, Chen Y, Mazzieri R, et al. Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J Biol Chem. 2003;278:2750–7.

    Article  PubMed  CAS  Google Scholar 

  41. Chaudhry SS, Cain SA, Morgan A, Dallas SL, Shuttleworth CA, Kielty CM. Fibrillin-1 regulates the bioavailability of TGFbeta1. J Cell Biol. 2007;176:355–67.

    Article  PubMed  CAS  Google Scholar 

  42. Dietz HC, Loeys B, Carta L, Ramirez F. Recent progress towards a molecular understanding of Marfan syndrome. Am J Med Genet C Semin Med Genet. 2005;139C:4–9.

    Article  PubMed  CAS  Google Scholar 

  43. ten Dijke DP, Arthur HM. Extracellular control of TGFbeta signalling in vascular development and disease. Nat Rev Mol Cell Biol. 2007;8:857–69.

    Article  PubMed  CAS  Google Scholar 

  44. Wipff PJ, Rifkin DB, Meister JJ, Hinz B. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol. 2007;179:1311–23.

    Article  PubMed  CAS  Google Scholar 

  45. Daniel CW, Robinson SD. Regulation of mammary growth and function by TGF-beta. Mol Reprod Dev. 1992;32:145–51.

    Article  PubMed  CAS  Google Scholar 

  46. Faure E, Heisterkamp N, Groffen J, Kaartinen V. Differential expression of TGF-beta isoforms during postlactational mammary gland involution. Cell Tissue Res. 2000;300:89–95.

    PubMed  CAS  Google Scholar 

  47. Robinson SD, Silberstein GB, Roberts AB, Flanders KC, Daniel CW. Regulated expression and growth inhibitory effects of transforming growth factor-beta isoforms in mouse mammary gland development. Development. 1991;113:867–78.

    PubMed  CAS  Google Scholar 

  48. Gorska AE, Joseph H, Derynck R, Moses HL, Serra R. Dominant-negative interference of the transforming growth factor beta type II receptor in mammary gland epithelium results in alveolar hyperplasia and differentiation in virgin mice. Cell Growth Differ. 1998;9:229–38.

    PubMed  CAS  Google Scholar 

  49. Kordon EC, McKnight RA, Jhappan C, Hennighausen L, Merlino G, Smith GH. Ectopic TGF beta 1 expression in the secretory mammary epithelium induces early senescence of the epithelial stem cell population. Dev Biol. 1995;168:47–61.

    Article  PubMed  CAS  Google Scholar 

  50. Robinson SD, Roberts AB, Daniel CW. TGF beta suppresses casein synthesis in mouse mammary explants and may play a role in controlling milk levels during pregnancy. J Cell Biol. 1993;120:245–51.

    Article  PubMed  CAS  Google Scholar 

  51. Atwood CS, Ikeda M, Vonderhaar BK. Involution of mouse mammary glands in whole organ culture: a model for studying programmed cell death. Biochem Biophys Res Commun. 1995;207:860–7.

    Article  PubMed  CAS  Google Scholar 

  52. Nguyen AV, Pollard JW. Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution. Development. 2000;127:3107–18.

    PubMed  CAS  Google Scholar 

  53. D’Cruz CM, Moody SE, Master SR, Hartman JL, Keiper EA, Imielinski MB, et al. Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland. Mol Endocrinol. 2002;16:2034–51.

    Article  PubMed  CAS  Google Scholar 

  54. Motyl T, Gajkowska B, Wojewodzka U, Wareski P, Rekiel A, Ploszaj T. Expression of apoptosis-related proteins in involuting mammary gland of sow. Comp Biochem Physiol B Biochem Mol Biol. 2001;128:635–46.

    Article  PubMed  CAS  Google Scholar 

  55. Plath A, Einspanier R, Peters F, Sinowatz F, Schams D. Expression of transforming growth factors alpha and beta-1 messenger RNA in the bovine mammary gland during different stages of development and lactation. J Endocinol. 1997;155:501–511.

    Article  CAS  Google Scholar 

  56. Wareski P, Motyl T, Ryniewicz Z, Orzechowski A, Gajkowska B, Wojewodzka U, et al. Expression of apoptosis-related proteins in mammary gland of goat. Small Rumin Res. 2001;40:279–89.

    Article  PubMed  Google Scholar 

  57. Li M, Liu X, Robinson G, Bar-Peled U, Wagner KU, Young WS, et al. Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution. Proc Natl Acad Sci U S A. 1997;94:3425–30.

    Article  PubMed  CAS  Google Scholar 

  58. Quarrie LH, Addey CV, Wilde CJ. Programmed cell death during mammary tissue involution induced by weaning, litter removal, and milk stasis. J Cell Physiol. 1996;168:559–69.

    Article  PubMed  CAS  Google Scholar 

  59. Sanchez-Capelo A. Dual role for TGF-beta1 in apoptosis. Cytokine Growth Factor Rev. 2005;16:15–34.

    Article  PubMed  CAS  Google Scholar 

  60. Yang YA, Tang B, Robinson G, Hennighausen L, Brodie SG, Deng CX, et al. Smad3 in the mammary epithelium has a nonredundant role in the induction of apoptosis, but not in the regulation of proliferation or differentiation by transforming growth factor-beta. Cell Growth Differ. 2002;13:123–30.

    PubMed  CAS  Google Scholar 

  61. Gorska AE, Jensen RA, Shyr Y, Aakre ME, Bhowmick NA, Moses HL. Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation. Am J Pathol. 2003;163:1539–49.

    PubMed  CAS  Google Scholar 

  62. Bailey JP, Nieport KM, Herbst MP, Srivastava S, Serra RA, Horseman ND. Prolactin and transforming growth factor-beta signaling exert opposing effects on mammary gland morphogenesis, involution, and the Akt-forkhead pathway. Mol Endocrinol. 2004;18:1171–84.

    Article  PubMed  CAS  Google Scholar 

  63. Bierie B, Gorska AE, Stover DG, Moses HL. TGF-beta promotes cell death and suppresses lactation during the second stage of mammary involution. J Cell Physiol. 2009;219:57–68.

    Article  PubMed  CAS  Google Scholar 

  64. Muraoka-Cook RS, Shin I, Yi JY, Easterly E, Barcellos-Hoff MH, Yingling JM, et al. Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene. 2006;25:3408–23.

    Article  PubMed  CAS  Google Scholar 

  65. Stein T, Salomonis N, Gusterson BA. Mammary gland involution as a multi-step process. J Mammary Gland Biol Neoplasia. 2007;12:25–35.

    Article  PubMed  Google Scholar 

  66. Kawamata H, Fujimori T, Imai Y. TSC-22 (TGF-beta stimulated clone-22): a novel molecular target for differentiation-inducing therapy in salivary gland cancer. Curr Cancer Drug Targets. 2004;4:521–9.

    Article  PubMed  CAS  Google Scholar 

  67. Shostak KO, Dmitrenko VV, Garifulin OM, Rozumenko VD, Khomenko OV, Zozulya YA, et al. Downregulation of putative tumor suppressor gene TSC-22 in human brain tumors. J Surg Oncol. 2003;82:57–64.

    Article  PubMed  CAS  Google Scholar 

  68. Schorr K, Li M, Krajewski S, Reed JC, Furth PA. Bcl-2 gene family and related proteins in mammary gland involution and breast cancer. J Mammary Gland Biol Neoplasia. 1999;4:153–64.

    Article  PubMed  CAS  Google Scholar 

  69. Teramoto T, Kiss A, Thorgeirsson SS. Induction of p53 and Bax during TGF-beta 1 initiated apoptosis in rat liver epithelial cells. Biochem Biophys Res Commun. 1998;251:56–60.

    Article  PubMed  CAS  Google Scholar 

  70. Xiao M, Oppenlander BK, Dooley DC. Transforming growth factor-beta(1) induces apoptosis in CD34(+) CD38(-/low) cells that express Bcl-2 at a low level. Exp Hematol. 2001;29:1098–108.

    Article  PubMed  CAS  Google Scholar 

  71. Chapman RS, Lourenco PC, Tonner E, Flint DJ, Selbert S, Takeda K, et al. Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. Genes Dev. 1999;13:2604–16.

    Article  PubMed  CAS  Google Scholar 

  72. 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.

    Article  PubMed  CAS  Google Scholar 

  73. 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.

    Article  PubMed  CAS  Google Scholar 

  74. Reibman J, Meixler S, Lee TC, Gold LI, Cronstein BN, Haines KA, et al. Transforming growth factor beta 1, a potent chemoattractant for human neutrophils, bypasses classic signal-transduction pathways. Proc Natl Acad Sci U S A. 1991;88:6805–9.

    Article  PubMed  CAS  Google Scholar 

  75. Wahl SM, Hunt DA, Wakefield LM, Cartney-Francis N, Wahl LM, Roberts AB, et al. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A. 1987;84:5788–92.

    Article  PubMed  CAS  Google Scholar 

  76. Parekh T, Saxena B, Reibman J, Cronstein BN, Gold LI. Neutrophil chemotaxis in response to TGF-beta isoforms (TGF-beta 1, TGF-beta 2, TGF-beta 3) is mediated by fibronectin. J Immunol. 1994;152:2456–66.

    PubMed  CAS  Google Scholar 

  77. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA. 1993;90:770–4.

    Article  PubMed  CAS  Google Scholar 

  78. Wahl SM, Wen J, Moutsopoulos N. TGF-beta: a mobile purveyor of immune privilege. Immunol Rev. 2006;213:213–27.

    Article  PubMed  CAS  Google Scholar 

  79. Ignotz RA, Massague J. Type beta transforming growth factor controls the adipogenic differentiation of 3T3 fibroblasts. Proc Natl Acad Sci U S A. 1985;82:8530–4.

    Article  PubMed  CAS  Google Scholar 

  80. Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986;83:4167–71.

    Article  PubMed  CAS  Google Scholar 

  81. Postlethwaite AE, Keski-Oja J, Moses HL, Kang AH. Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. J Exp Med. 1987;165:251–6.

    Article  PubMed  CAS  Google Scholar 

  82. Cordeiro MF, Bhattacharya SS, Schultz GS, Khaw PT. TGF-beta1, -beta2, and -beta3 in vitro: biphasic effects on Tenon’s fibroblast contraction, proliferation, and migration. Invest Ophthalmol Vis Sci. 2000;41:756–63.

    PubMed  CAS  Google Scholar 

  83. Schor SL, Ellis IR, Harada K, Motegi K, Anderson AR, Chaplain MA, et al. A novel ‘sandwich’ assay for quantifying chemo-regulated cell migration within 3-dimensional matrices: wound healing cytokines exhibit distinct motogenic activities compared to the transmembrane assay. Cell Motil Cytoskeleton. 2006;63:287–300.

    Article  PubMed  CAS  Google Scholar 

  84. Serini G, Gabbiani G. Modulation of alpha-smooth muscle actin expression in fibroblasts by transforming growth factor-beta isoforms: an in vivo and in vitro study. Wound Repair Regen. 1996;4:278–87.

    Article  PubMed  CAS  Google Scholar 

  85. 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.

    Article  PubMed  CAS  Google Scholar 

  86. Albrektsen G, Heuch I, Hansen S, Kvale G. Breast cancer risk by age at birth, time since birth and time intervals between births: exploring interaction effects. Br J Cancer. 2005;92:167–75.

    Article  PubMed  CAS  Google Scholar 

  87. Whiteman MK, Hillis SD, Curtis KM, McDonald JA, Wingo PA, Marchbanks PA. Reproductive history and mortality after breast cancer diagnosis. Obstet Gynecol. 2004;104:146–54.

    PubMed  Google Scholar 

  88. Bemis LT, Schedin P. Reproductive state of rat mammary gland stroma modulates human breast cancer cell migration and invasion. Cancer Res. 2000;60:3414–8.

    PubMed  CAS  Google Scholar 

  89. Schedin P, Mitrenga T, McDaniel S, Kaeck M. Mammary ECM composition and function are altered by reproductive state. Mol Carcinog. 2004;41:207–20.

    Article  PubMed  CAS  Google Scholar 

  90. Blakely CM, Stoddard AJ, Belka GK, Dugan KD, Notarfrancesco KL, Moody SE, et al. Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy. Cancer Res. 2006;66:6421–31.

    Article  PubMed  CAS  Google Scholar 

  91. Roberts AB, Wakefield LM. The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci U S A. 2003;100:8621–3.

    Article  PubMed  CAS  Google Scholar 

  92. Pardali K, Moustakas A. Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta. 2007;1775:21–62.

    PubMed  CAS  Google Scholar 

  93. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.

    Article  PubMed  CAS  Google Scholar 

  94. Yang L, Moses HL. Transforming growth factor beta: tumor suppressor or promoter? Are host immune cells the answer? Cancer Res. 2008;68:9107–11.

    Article  PubMed  CAS  Google Scholar 

  95. Shah M, Foreman DM, Ferguson MW. Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J Cell Sci. 1995;108:985–1002.

    PubMed  CAS  Google Scholar 

  96. Lindelof B, Krynitz B, Granath F, Ekbom A. Burn injuries and skin cancer: a population-based cohort study. Acta Derm Venereol. 2008;88:20–2.

    Article  PubMed  Google Scholar 

  97. Mellemkjaer L, Holmich LR, Gridley G, Rabkin C, Olsen JH. Risks for skin and other cancers up to 25 years after burn injuries. Epidemiology. 2006;17:668–73.

    Article  PubMed  Google Scholar 

  98. Madri JA, Bell L, Merwin JR. Modulation of vascular cell behavior by transforming growth factors beta. Mol Reprod Dev. 1992;32:121–6.

    Article  PubMed  CAS  Google Scholar 

  99. Shinozaki M, Kawara S, Hayashi N, Kakinuma T, Igarashi A, Takehara K. Induction of subcutaneous tissue fibrosis in newborn mice by transforming growth factor beta—simultaneous application with basic fibroblast growth factor causes persistent fibrosis. Biochem Biophys Res Commun. 1997;240:292–7.

    Article  PubMed  CAS  Google Scholar 

  100. Whitby DJ, Ferguson MW. Immunohistochemical localization of growth factors in fetal wound healing. Dev Biol. 1991;147:207–15.

    Article  PubMed  CAS  Google Scholar 

  101. Whitby DJ, Ferguson MW. The extracellular matrix of lip wounds in fetal, neonatal and adult mice. Development. 1991;112:651–68.

    PubMed  CAS  Google Scholar 

  102. Occleston NL, O'Kane S, Goldspink N, Ferguson MW. New therapeutics for the prevention and reduction of scarring. Drug Discov Today. 2008;13:973–81.

    Article  PubMed  CAS  Google Scholar 

  103. Cox DG, Penney K, Guo Q, Hankinson SE, Hunter DJ. TGFB1 and TGFBR1 polymorphisms and breast cancer risk in the Nurses’ Health Study. BMC Cancer. 2007;7:175.

    Article  PubMed  CAS  Google Scholar 

  104. Jugessur A, Lie RT, Wilcox AJ, Murray JC, Taylor JA, Saugstad OD, et al. Variants of developmental genes (TGFA, TGFB3, and MSX1) and their associations with orofacial clefts: a case-parent triad analysis. Genet Epidemiol. 2003;24:230–9.

    Article  PubMed  Google Scholar 

  105. Veer LJ Van’t, 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.

    Article  Google Scholar 

  106. Van Obberghen-Schilling E, Roche NS, Flanders KC, Sporn MB, Roberts AB. Transforming growth factor beta 1 positively regulates its own expression in normal and transformed cells. J Biol Chem. 1988;263:7741–6.

    PubMed  Google Scholar 

  107. Bascom CC, Wolfshohl JR, Coffey RJ Jr, Madisen L, Webb NR, Purchio AR, et al. Complex regulation of transforming growth factor beta 1, beta 2, and beta 3 mRNA expression in mouse fibroblasts and keratinocytes by transforming growth factors beta 1 and beta 2. Mol Cell Biol. 1989;9:5508–15.

    PubMed  CAS  Google Scholar 

  108. Rolfe KJ, Irvine LM, Grobbelaar AO, Linge C. Differential gene expression in response to transforming growth factor-beta1 by fetal and postnatal dermal fibroblasts. Wound Repair Regen. 2007;15:897–906.

    Article  PubMed  Google Scholar 

  109. Grotendorst GR. Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev. 1997;8:171–7.

    Article  PubMed  CAS  Google Scholar 

  110. Jimenez SA, Varga J, Olsen A, Li L, Diaz A, Herhal J, et al. Functional analysis of human alpha 1(I) procollagen gene promoter. Differential activity in collagen-producing and -nonproducing cells and response to transforming growth factor beta 1. J Biol Chem. 1994;269:12684–91.

    PubMed  CAS  Google Scholar 

  111. Verrecchia F, Chu ML, Mauviel A. Identification of novel TGF-beta /Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem. 2001;276:17058–62.

    Article  PubMed  CAS  Google Scholar 

  112. Kahari VM, Peltonen J, Chen YQ, Uitto J. Differential modulation of basement membrane gene expression in human fibrosarcoma HT-1080 cells by transforming growth factor-beta 1. Enhanced type IV collagen and fibronectin gene expression correlates with altered culture phenotype of the cells. Lab Invest. 1991;64:807–18.

    PubMed  CAS  Google Scholar 

  113. Paralkar VM, Vukicevic S, Reddi AH. Transforming growth factor beta type 1 binds to collagen IV of basement membrane matrix: implications for development. Dev Biol. 1991;143:303–8.

    Article  PubMed  CAS  Google Scholar 

  114. Kahai S, Vary CP, Gao Y, Seth A. Collagen, type V, alpha1 (COL5A1) is regulated by TGF-beta in osteoblasts. Matrix Biol. 2004;23:445–55.

    Article  PubMed  CAS  Google Scholar 

  115. Kivirikko S, Mauviel A, Pihlajaniemi T, Uitto J. Cytokine modulation of type XV collagen gene expression in human dermal fibroblast cultures. Exp Dermatol. 1999;8:407–12.

    Article  PubMed  CAS  Google Scholar 

  116. Vaisanen T, Vaisanen MR, Utio-Harmainen H, Pihlajaniemi T. Type XIII collagen expression is induced during malignant transformation in various epithelial and mesenchymal tumours. J Pathol. 2005;207:324–35.

    Article  PubMed  CAS  Google Scholar 

  117. Quaglino D Jr, Nanney LB, Kennedy R, Davidson JM. Transforming growth factor-beta stimulates wound healing and modulates extracellular matrix gene expression in pig skin. I. Excisional wound model. Lab Invest. 1990;63:307–19.

    PubMed  CAS  Google Scholar 

  118. Raghunath M, Unsold C, Kubitscheck U, Bruckner-Tuderman L, Peters R, Meuli M. The cutaneous microfibrillar apparatus contains latent transforming growth factor-beta binding protein-1 (LTBP-1) and is a repository for latent TGF-beta1. J Invest Dermatol. 1998;111:559–64.

    Article  PubMed  CAS  Google Scholar 

  119. Lorena D, Darby IA, Reinhardt DP, Sapin V, Rosenbaum J, Desmouliere A. Fibrillin-1 expression in normal and fibrotic rat liver and in cultured hepatic fibroblastic cells: modulation by mechanical stress and role in cell adhesion. Lab Invest. 2004;84:203–12.

    Article  PubMed  CAS  Google Scholar 

  120. Saharinen J, Hyytiainen M, Taipale J, Keski-Oja J. Latent transforming growth factor-beta binding proteins (LTBPs)- structural extracellular matrix proteins for targeting TGF-beta action. Cytokine Growth Factor Rev. 1999;10:99–117.

    Article  PubMed  CAS  Google Scholar 

  121. Border WA, Okuda S, Languino LR, Ruoslahti E. Transforming growth factor-beta regulates production of proteoglycans by mesangial cells. Kidney Int. 1990;37:689–95.

    Article  PubMed  CAS  Google Scholar 

  122. Stander M, Naumann U, Wick W, Weller M. Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth. Cell Tissue Res. 1999;296:221–7.

    Article  PubMed  CAS  Google Scholar 

  123. Saika S, Miyamoto T, Tanaka S, Tanaka T, Ishida I, Ohnishi Y, et al. Response of lens epithelial cells to injury: role of lumican in epithelial-mesenchymal transition. Invest Ophthalmol Vis Sci. 2003;44:2094–102.

    Article  PubMed  Google Scholar 

  124. Kolb M, Margetts PJ, Sime PJ, Gauldie J. Proteoglycans decorin and biglycan differentially modulate TGF-beta-mediated fibrotic responses in the lung. Am J Physiol Lung Cell Mol Physiol. 2001;280:L1327–34.

    PubMed  CAS  Google Scholar 

  125. Eichler W, Friedrichs U, Thies A, Tratz C, Wiedemann P. Modulation of matrix metalloproteinase and TIMP-1 expression by cytokines in human RPE cells. Invest Ophthalmol Vis Sci. 2002;43:2767–73.

    PubMed  Google Scholar 

  126. Maretzky T, Scholz F, Koten B, Proksch E, Saftig P, Reiss K. ADAM10-mediated E-cadherin release is regulated by proinflammatory cytokines and modulates keratinocyte cohesion in eczematous dermatitis. J Invest Dermatol. 2008;128:1737–46.

    Article  PubMed  CAS  Google Scholar 

  127. Cross NA, Chandrasekharan S, Jokonya N, Fowles A, Hamdy FC, Buttle DJ, et al. The expression and regulation of ADAMTS-1, -4, -5, -9, and -15, and TIMP-3 by TGFbeta1 in prostate cells: relevance to the accumulation of versican. Prostate. 2005;63:269–75.

    Article  PubMed  CAS  Google Scholar 

  128. Murphy-Ullrich JE, Schultz-Cherry S, Hook M. Transforming growth factor-beta complexes with thrombospondin. Mol Biol Cell. 1992;3:181–8.

    PubMed  CAS  Google Scholar 

  129. Penttinen RP, Kobayashi S, Bornstein P. Transforming growth factor beta increases mRNA for matrix proteins both in the presence and in the absence of changes in mRNA stability. Proc Natl Acad Sci U S A. 1988;85:1105–8.

    Article  PubMed  CAS  Google Scholar 

  130. Francki A, Bradshaw AD, Bassuk JA, Howe CC, Couser WG, Sage EH. SPARC regulates the expression of collagen type I and transforming growth factor-beta1 in mesangial cells. J Biol Chem. 1999;274:32145–52.

    Article  PubMed  CAS  Google Scholar 

  131. Wrana JL, Overall CM, Sodek J. Regulation of the expression of a secreted acidic protein rich in cysteine (SPARC) in human fibroblasts by transforming growth factor beta. Comparison of transcriptional and post-transcriptional control with fibronectin and type I collagen. Eur J Biochem. 1991;197:519–28.

    Article  PubMed  CAS  Google Scholar 

  132. Erkan M, Kleeff J, Gorbachevski A, Reiser C, Mitkus T, Esposito I, et al. Periostin creates a tumor-supportive microenvironment in the pancreas by sustaining fibrogenic stellate cell activity. Gastroenterology. 2007;132:1447–64.

    Article  PubMed  CAS  Google Scholar 

  133. Horiuchi K, Amizuka N, Takeshita S, Takamatsu H, Katsuura M, Ozawa H, et al. Identification and characterization of a novel protein, periostin, with restricted expression to periosteum and periodontal ligament and increased expression by transforming growth factor beta. J Bone Miner Res. 1999;14:1239–49.

    Article  PubMed  CAS  Google Scholar 

  134. Lesne S, Docagne F, Gabriel C, Liot G, Lahiri DK, Buee L, et al. Transforming growth factor-beta 1 potentiates amyloid-beta generation in astrocytes and in transgenic mice. J Biol Chem. 2003;278:18408–18.

    Article  PubMed  CAS  Google Scholar 

  135. Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A, et al. 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. 2005;102:13550–5.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Mary Helen Barcellos-Hoff for critically reading the manuscript.

Author information

Authors and Affiliations

  1. Laboratory of Cancer Biology & Genetics, National Cancer Institute, Bethesda, MD, USA

    Kathleen C. Flanders & Lalage M. Wakefield

  2. Laboratory of Cancer Biology & Genetics, National Cancer Institute, National Institutes of Health, Bldg 37/ Rm 5046B, 37 Convent Dr, Bethesda, MD, 20892, USA

    Kathleen C. Flanders

Authors
  1. Kathleen C. Flanders
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lalage M. Wakefield
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathleen C. Flanders.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Flanders, K.C., Wakefield, L.M. Transforming Growth Factor-βs and Mammary Gland Involution; Functional Roles and Implications for Cancer Progression. J Mammary Gland Biol Neoplasia 14, 131–144 (2009). https://doi.org/10.1007/s10911-009-9122-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-009-9122-z

Keywords

Search

Navigation