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TGFβ as a Potential Mediator of Progesterone Action in the Mammary Gland of Pregnancy

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

The molecular mechanisms controlling the onset of copious milk secretion are only now beginning to be elucidated. We have known for nearly four decades that progesterone suppresses milk secretion during pregnancy, and that the fall in progesterone near parturition is necessary for secretory activation. Similarly, we’ve known for 15 years that transforming growth factor β (TGFβ) also suppresses milk secretion. Yet no formal link between the two has ever been established. This work aims to review the evidence for and against a link between progesterone and TGFβ, raise unanswered questions, and to propose further lines of research.

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Abbreviations

TGFβ:

transforming growth factor beta

BMP:

bone morphogenic protein

MMP:

matrix metalloproteinase

TIMP:

tissue-inhibitor of metalloproteinase

LAP:

latency-associated peptide

Smad:

Mad-homolog

TβRI:

type I TGFβ receptor

TβRII:

type II TGFβ receptor

PR:

progesterone receptor

ER:

estrogen receptor

AR:

androgen receptor

IGF:

insulin-like growth factor

MEC:

mammary epithelial cell

SBE:

Smad-binding element

EMT:

epithelial to mesenchymal transition

MET:

mesenchymal to epithelial transition

MAPK:

mitogen-activated kinase

P4:

progesterone,

JNK:

the c-Jun NH2 terminal kinase

PI3K:

phosphatidylinositol kinase

TAK1:

TGFβ-activated kinase

PP2A:

protein phosphatase 2A

Par6:

partitioning-defective protein 6

DAXX:

death-associated protein 6

IGFBP:

insulin-like growth factor binding protein

LRP:

low-density lipoprotein-related receptor

WAP:

whey acidic protein

VDR:

vitamin D receptor

PMEC:

primary mammary epithelial cells

SGAGs:

sulfated glycosaminoglycans

AP2B1:

adaptor-related protein complex 2, beta 1 subunit

FKBP1A:

FK506 binding protein 1A (12 kDa)

STRAP:

serine–threonine–kinase receptor-associated protein

ZAK:

sterile alpha motif and leucine zipper containing kinase AZK

SMURF2:

Smad specific E3 ubiquitin ligase 2

References

  1. Schiller M, Javelaud D, Mauviel A. TGF-beta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing. J Dermatol Sci 2004;35(2):83–92.

    Article  PubMed  CAS  Google Scholar 

  2. Jobling MF, Mott JD, Finnegan MT, Jurukovski V, Erickson AC, Walian PJ, et al. Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species. Radiat Res 2006;166(6):839–48.

    Article  PubMed  CAS  Google Scholar 

  3. Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. Embo J 1998;17(11):3091–100.

    Article  PubMed  CAS  Google Scholar 

  4. Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 2006;6(7):506–20.

    Article  PubMed  CAS  Google Scholar 

  5. Moustakas A, Souchelnytskyi S, Heldin CH. Smad regulation in TGF-beta signal transduction. J Cell Sci 2001;114(Pt 24):4359–69.

    PubMed  CAS  Google Scholar 

  6. Brown KA, Pietenpol JA, Moses HL. A tale of two proteins: differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling. J Cell Biochem 2007;101(1):9–33.

    Article  PubMed  CAS  Google Scholar 

  7. Xiao YQ, Malcolm K, Worthen GS, Gardai S, Schiemann WP, Fadok VA, et al. Cross-talk between ERK and p38 MAPK mediates selective suppression of pro-inflammatory cytokines by transforming growth factor-beta. J Biol Chem 2002;277(17):14884–93.

    Article  PubMed  CAS  Google Scholar 

  8. Edlund S, Landstrom M, Heldin CH, Aspenstrom P. Transforming growth factor-beta-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol Biol Cell 2002;13(3):902–14.

    Article  PubMed  CAS  Google Scholar 

  9. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425(6958):577–84.

    Article  PubMed  CAS  Google Scholar 

  10. Danielpour D, Song K. Cross-talk between IGF-I and TGF-beta signaling pathways. Cytokine Growth Factor Rev 2006;17(1–2):59–74.

    Article  PubMed  CAS  Google Scholar 

  11. Zhang F, Laiho M. On and off: proteasome and TGF-beta signaling. Exp Cell Res 2003;291(2):275–81.

    Article  PubMed  CAS  Google Scholar 

  12. Massague J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. Embo J 2000;19(8):1745–54.

    Article  PubMed  CAS  Google Scholar 

  13. Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS, et al. High-throughput mapping of a dynamic signaling network in mammalian cells. Science 2005;307(5715):1621–5.

    Article  PubMed  CAS  Google Scholar 

  14. Sauer B, Vogler R, von Wenckstern H, Fujii M, Anzano MB, Glick AB, et al. Involvement of Smad signaling in sphingosine 1-phosphate-mediated biological responses of keratinocytes. J Biol Chem 2004;279(37):38471–9.

    Article  PubMed  CAS  Google Scholar 

  15. Xin C, Ren S, Kleuser B, Shabahang S, Eberhardt W, Radeke H, et al. Sphingosine 1-phosphate cross-activates the Smad signaling cascade and mimics transforming growth factor-beta-induced cell responses. J Biol Chem 2004;279(34):35255–62.

    Article  PubMed  CAS  Google Scholar 

  16. Cho KW, Kim JY, Song SJ, Farrell E, Eblaghie MC, Kim HJ, et al. Molecular interactions between Tbx3 and Bmp4 and a model for dorsoventral positioning of mammary gland development. Proc Natl Acad Sci U S A 2006;103(45):16788–93.

    Article  PubMed  CAS  Google Scholar 

  17. Hens JR, Dann P, Zhang JP, Harris S, Robinson GW, Wysolmerski J. BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction. Development 2007;134(6):1221–30.

    Article  PubMed  CAS  Google Scholar 

  18. Daniel CW, Robinson S, Silberstein GB. The transforming growth factors beta in development and functional differentiation of the mouse mammary gland. Adv Exp Med Biol 2001;501:61–70.

    PubMed  CAS  Google Scholar 

  19. Hinck L, Silberstein GB. Key stages in mammary gland development: the mammary end bud as a motile organ. Breast Cancer Res 2005;7(6):245–51.

    Article  PubMed  CAS  Google Scholar 

  20. Serra R, Crowley MR. Mouse models of transforming growth factor beta impact in breast development and cancer. Endocr Relat Cancer 2005;12(4):749–60.

    Article  PubMed  CAS  Google Scholar 

  21. Buck MB, Knabbe C. TGF-beta signaling in breast cancer. Ann N Y Acad Sci 2006;1089:119–26.

    Article  PubMed  CAS  Google Scholar 

  22. Fleisch MC, Maxwell CA, Barcellos-Hoff MH. The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs. Endocr Relat Cancer 2006;13(2):379–400.

    Article  PubMed  CAS  Google Scholar 

  23. Barcellos-Hoff MH, Medina D. New highlights on stroma–epithelial interactions in breast cancer. Breast Cancer Res 2005;7(1):33–6.

    Article  PubMed  CAS  Google Scholar 

  24. Neville MC, McFadden TB, Forsyth I. Hormonal regulation of mammary differentiation and milk secretion. J Mammary Gland Biol Neoplasia 2002;7(1):49–66.

    Article  PubMed  Google Scholar 

  25. Schedin P, Mitrenga T, Kaeck M. Estrous cycle regulation of mammary epithelial cell proliferation, differentiation, and death in the Sprague–Dawley rat: a model for investigating the role of estrous cycling in mammary carcinogenesis. J Mammary Gland Biol Neoplasia 2000;5(2):211–25.

    Article  PubMed  CAS  Google Scholar 

  26. Fata JE, Chaudhary V, Khokha R. Cellular turnover in the mammary gland is correlated with systemic levels of progesterone and not 17beta-estradiol during the estrous cycle. Biol Reprod 2001;65(3):680–8.

    Article  PubMed  CAS  Google Scholar 

  27. Neifert MR, McDonough SL, Neville MC. Failure of lactogenesis associated with placental retention. Am J Obstet Gynecol 1981;140(4):477–8.

    PubMed  CAS  Google Scholar 

  28. Nguyen DA, Parlow AF, Neville MC. Hormonal regulation of tight junction closure in the mouse mammary epithelium during the transition from pregnancy to lactation. J Endocrinol 2001;170(2):347–56.

    Article  PubMed  CAS  Google Scholar 

  29. Murphy G, Ariyanayagam AD, Kuhn NJ. Progesterone and the metabolic control of the lactose biosynthetic pathway during lactogenesis in the rat. Biochem J 1973;136(4):1105–16.

    PubMed  CAS  Google Scholar 

  30. Buser AC, Gass-Handel EK, Wyszomierski SL, Doppler W, Leonhardt SA, Schaack J, et al. Progesterone receptor repression of prolactin/signal transducer and activator of transcription 5-mediated transcription of the beta-casein gene in mammary epithelial cells. Mol Endocrinol 2007;21(1):106–25.

    Article  PubMed  CAS  Google Scholar 

  31. Silberstein GB, Van Horn K, Shyamala G, Daniel CW. Progesterone receptors in the mouse mammary duct: distribution and developmental regulation. Cell Growth Differ 1996;7(7):945–52.

    PubMed  CAS  Google Scholar 

  32. Ewan KB, Shyamala G, Ravani SA, Tang Y, Akhurst R, Wakefield L, et al. Latent transforming growth factor-beta activation in mammary gland: regulation by ovarian hormones affects ductal and alveolar proliferation. Am J Pathol 2002;160(6):2081–93.

    PubMed  CAS  Google Scholar 

  33. Kariagina A, Aupperlee MD, Haslam SZ. Progesterone receptor isoforms and proliferation in the rat mammary gland during development. Endocrinology 2007;148(6):2723–36.

    Article  PubMed  CAS  Google Scholar 

  34. Schams D, Kohlenberg S, Amselgruber W, Berisha B, Pfaffl MW, Sinowatz F. Expression and localisation of oestrogen and progesterone receptors in the bovine mammary gland during development, function and involution. J Endocrinol 2003;177(2):305–17.

    Article  PubMed  CAS  Google Scholar 

  35. Ismail PM, Li J, DeMayo FJ, O'Malley BW, Lydon JP. A novel LacZ reporter mouse reveals complex regulation of the progesterone receptor promoter during mammary gland development. Mol Endocrinol 2002;16(11):2475–89.

    Article  PubMed  CAS  Google Scholar 

  36. Daniel CW, Robinson SD. Regulation of mammary growth and function by TGF-beta. Mol Reprod Dev 1992;32(2):145–51.

    Article  PubMed  CAS  Google Scholar 

  37. 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(3):867–78.

    PubMed  CAS  Google Scholar 

  38. Strange R, Li F, Saurer S, Burkhardt A, Friis RR. Apoptotic cell death and tissue remodelling during mouse mammary gland involution. Development 1992;115(1):49–58.

    PubMed  CAS  Google Scholar 

  39. Boulanger CA, Wagner KU, Smith GH. Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta1 expression. Oncogene 2005;24(4):552–60.

    Article  PubMed  CAS  Google Scholar 

  40. Zhang M, Zola H, Read L, Penttila I. Identification of soluble transforming growth factor-beta receptor III (sTbetaIII) in rat milk. Immunol Cell Biol 2001;79(3):291–7.

    Article  PubMed  CAS  Google Scholar 

  41. Hawkes JS, Bryan DL, Gibson RA. Variations in transforming growth factor beta in human milk are not related to levels in plasma. Cytokine 2002;17(4):182–6.

    Article  PubMed  CAS  Google Scholar 

  42. Laiho K, Lampi AM, Hamalainen M, Moilanen E, Piironen V, Arvola T, et al. Breast milk fatty acids, eicosanoids, and cytokines in mothers with and without allergic disease. Pediatr Res 2003;53(4):642–7.

    Article  PubMed  CAS  Google Scholar 

  43. Thompson HG, Mih JD, Krasieva TB, Tromberg BJ, George SC. Epithelial-derived TGF-beta2 modulates basal and wound-healing subepithelial matrix homeostasis. Am J Physiol Lung Cell Mol Physiol 2006;291(6):L1277–85.

    Article  PubMed  CAS  Google Scholar 

  44. Shynlova O, Tsui P, Dorogin A, Langille BL, Lye SJ. The expression of transforming growth factor beta in pregnant rat myometrium is hormone and stretch dependent. Reproduction 2007;134(3):503–11.

    Article  PubMed  CAS  Google Scholar 

  45. Nguyen AV, Pollard JW. Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution. Development 2000;127(14):3107–18.

    PubMed  CAS  Google Scholar 

  46. 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(1):245–51.

    Article  PubMed  CAS  Google Scholar 

  47. Faure E, Heisterkamp N, Groffen J, Kaartinen V. Differential expression of TGF-beta isoforms during postlactational mammary gland involution. Cell Tissue Res 2000;300(1):89–95.

    PubMed  CAS  Google Scholar 

  48. Wilde CJ, Addey CV, Boddy LM, Peaker M. Autocrine regulation of milk secretion by a protein in milk. Biochem J 1995;305(Pt 1):51–8.

    PubMed  CAS  Google Scholar 

  49. 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(5):1171–84.

    Article  PubMed  CAS  Google Scholar 

  50. Schwertfeger KL, McManaman JL, Palmer CA, Neville MC, Anderson SM. Expression of constitutively activated Akt in the mammary gland leads to excess lipid synthesis during pregnancy and lactation. J Lipid Res 2003;44(6):1100–12.

    Article  PubMed  CAS  Google Scholar 

  51. 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(3):323–36.

    PubMed  CAS  Google Scholar 

  52. Zavadil J, Narasimhan M, Blumenberg M, Schneider RJ. Transforming growth factor-beta and microRNA:mRNA regulatory networks in epithelial plasticity. Cells Tissues Organs 2007;185(1–3):157–61.

    Article  PubMed  CAS  Google Scholar 

  53. 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(3):229–38.

    PubMed  CAS  Google Scholar 

  54. Sotgia F, Schubert W, Pestell RG, Lisanti MP. Genetic ablation of caveolin-1 in mammary epithelial cells increases milk production and hyper-activates STAT5a signaling. Cancer Biol Ther 2006;5(3):292–7.

    Article  PubMed  CAS  Google Scholar 

  55. Razani B, Zhang XL, Bitzer M, von Gersdorff G, Bottinger EP, Lisanti MP. Caveolin-1 regulates transforming growth factor (TGF)-beta/SMAD signaling through an interaction with the TGF-beta type I receptor. J Biol Chem 2001;276(9):6727–38.

    Article  PubMed  CAS  Google Scholar 

  56. Zinser GM, Welsh J. Accelerated mammary gland development during pregnancy and delayed postlactational involution in vitamin D3 receptor null mice. Mol Endocrinol 2004;18(9):2208–23.

    Article  PubMed  CAS  Google Scholar 

  57. Dibrov A, Kashour T, Amara FM. The role of transforming growth factor beta signaling in messenger RNA stability. Growth Factors 2006;24(1):1–11.

    Article  PubMed  CAS  Google Scholar 

  58. Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 2005;307(5715):1603–9.

    Article  PubMed  CAS  Google Scholar 

  59. Luo XH, Liao EY, Su X. Progesterone upregulates TGF-b isoforms (b1, b2, and b3) expression in normal human osteoblast-like cells. Calcif Tissue Int 2002;71(4):329–34.

    Article  PubMed  CAS  Google Scholar 

  60. Pollard JW, Hennighausen L. Colony stimulating factor 1 is required for mammary gland development during pregnancy. Proc Natl Acad Sci U S A 1994;91(20):9312–6.

    Article  PubMed  CAS  Google Scholar 

  61. Gouon-Evans V, Rothenberg ME, Pollard JW. Postnatal mammary gland development requires macrophages and eosinophils. Development 2000;127(11):2269–82.

    PubMed  CAS  Google Scholar 

  62. Zarzynska J, Gajewska M, Motyl T. Effects of hormones and growth factors on TGF-beta1 expression in bovine mammary epithelial cells. J Dairy Res 2005;72(1):39–48.

    Article  PubMed  CAS  Google Scholar 

  63. 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 Endocrinol 1997;155(3):501–11.

    Article  PubMed  CAS  Google Scholar 

  64. Richter JD. CPEB: a life in translation. Trends Biochem Sci 2007;32(6):279–85.

    Article  PubMed  CAS  Google Scholar 

  65. Brisken C, Park S, Vass T, Lydon JP, O'Malley BW, Weinberg RA. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc Natl Acad Sci U S A 1998;95(9):5076–81.

    Article  PubMed  CAS  Google Scholar 

  66. Rustom A, Saffrich R, Markovic I, Walther P, Gerdes HH. Nanotubular highways for intercellular organelle transport. Science 2004;303(5660):1007–10.

    Article  PubMed  CAS  Google Scholar 

  67. Onfelt B, Purbhoo MA, Nedvetzki S, Sowinski S, Davis DM. Long-distance calls between cells connected by tunneling nanotubules. Sci STKE 2005;2005(313):pe55.

    Article  PubMed  Google Scholar 

  68. Wustner D. Plasma membrane sterol distribution resembles the surface topography of living cells. Mol Biol Cell 2007;18(1):211–28.

    Article  PubMed  CAS  Google Scholar 

  69. Akhurst RJ. TGF-beta antagonists: why suppress a tumor suppressor? J Clin Invest 2002;109(12):1533–6.

    Article  PubMed  CAS  Google Scholar 

  70. Schiemann WP. Targeted TGF-beta chemotherapies: friend or foe in treating human malignancies? Expert Rev Anticancer Ther 2007;7(5):609–11.

    Article  PubMed  CAS  Google Scholar 

  71. Katz E, Streuli CH. The extracellular matrix as an adhesion checkpoint for mammary epithelial function. Int J Biochem Cell Biol 2007;39(4):715–26.

    Article  PubMed  CAS  Google Scholar 

  72. Rudolph MC, McManaman JL, Hunter L, Phang T, Neville MC. Functional development of the mammary gland: use of expression profiling and trajectory clustering to reveal changes in gene expression during pregnancy, lactation, and involution. J Mammary Gland Biol Neoplasia 2003;8(3):287–307.

    Article  PubMed  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(2):R75–R91.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Owing to space limitations, only selected works from the literature have been cited. Sincere apologies to those colleagues with relevant publications that were missed. This work was supported by NIH PO1-HD38129, Margaret C. Neville, PI.

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  1. Department of Physiology and Biophysics, MS 8309, University of Colorado Health Sciences, Anschutz Medical Campus, P.O. Box 6511, 12800 E. 19th Avenue, Aurora, CO, 80045, USA

    Jenifer Monks

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  1. Jenifer Monks
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Correspondence to Jenifer Monks.

Additional information

This work was supported by NIH PO1-HD38129, Margaret C. Neville, PI.

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Monks, J. TGFβ as a Potential Mediator of Progesterone Action in the Mammary Gland of Pregnancy. J Mammary Gland Biol Neoplasia 12, 249–257 (2007). https://doi.org/10.1007/s10911-007-9056-2

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