Parathyroid Hormone-Related Protein Specifies the Mammary Mesenchyme and Regulates Embryonic Mammary Development

  • Minoti Hiremath
  • John Wysolmerski


Parathyroid Hormone related Protein (PTHrP) is a critical regulator of mammary gland morphogenesis in the mouse embryo. Loss of PTHrP, or its receptor, PTHR1, results in arrested mammary buds at day 15 of embryonic development (E15). In contrast, overexpression of PTHrP converts the ventral epidermis into hairless nipple skin. PTHrP signaling appears to be critical for mammary mesenchyme specification, which in turn maintains mammary epithelial identity, directs bud outgrowth, disrupts the male mammary rudiment and specifies the formation of the nipple. In the embryonic mammary bud, PTHrP exerts its effects on morphogenesis, in part, through epithelial-stromal crosstalk mediated by Wnt and BMP signaling. Recently, PTHLH has been identified as a strong candidate for a novel breast cancer susceptibility locus, although PTHrP’s role in breast cancer has not been clearly defined. The effects of PTHrP on the growth of the embryonic mammary rudiment and its invasion into the dermis may, in turn, have connections to the role of PTHrP in breast cancer.


PTHrP Mammary Development Embryonic Breast Wnt Bmp 



Parathyroid hormone related protein


Keratin 14


Parathyroid hormone receptor, type I




Androgen receptor


Estrogen receptor


Bone morphogenic protein


Matrix metalloprotease



JW is supported by National Institutes of Health (NIH) grants R01 DK55501, R01 CA153702 and R01 DK077565. MH is supported by the Idaho INBRE Program [P20 RR016454 and P20GM103408] and by a postdoctoral fellowship from the Department of Defense Breast Cancer Research program (W81XWH-09-1-0580). We would like to thank Dr. Kata Granic for providing images of PTHrP-lacZ embryos.


  1. 1.
    Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, et al. Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide. N Engl J Med. 1988;319(9):556–63.PubMedCrossRefGoogle Scholar
  2. 2.
    Philbrick WM, Wysolmerski JJ, Galbraith S, Holt E, Orloff JJ, Yang KH, et al. Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev. 1996;76(1):127–73.PubMedGoogle Scholar
  3. 3.
    Jüppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991;254(5034):1024–6.PubMedCrossRefGoogle Scholar
  4. 4.
    McCauley LK, Martin TJ. Twenty-five years of PTHrP progress: from cancer hormone to multifunctional cytokine. J Bone Miner Res. 2012;27(6):1231–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Wysolmerski JJ. Interactions between breast, bone, and brain regulate mineral and skeletal metabolism during lactation. Ann N Y Acad Sci. 2010;1192:161–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Wysolmerski JJ. Parathyroid hormone-related protein: an update. J Clin Endocrinol Metab. 2012;97(9):2947–56.PubMedCrossRefGoogle Scholar
  7. 7.
    Chen X, Macica CM, Dreyer BE, Hammond VE, Hens JR, Philbrick WM, et al. Initial characterization of PTH-related protein gene-driven lacZ expression in the mouse. J Bone Miner Res. 2006;21(1):113–23.PubMedCrossRefGoogle Scholar
  8. 8.
    Boras-Granic K, Vanhouten J, Hiremath M, Wysolmerski J. Parathyroid hormone-related protein is not required for normal ductal or alveolar development in the post-natal mammary gland. PLoS One. 2011;6(11):e27278.PubMedCrossRefGoogle Scholar
  9. 9.
    Wansbury O, Mackay A, Kogata N, Mitsopoulos C, Kendrick H, Davidson K, et al. Transcriptome analysis of embryonic mammary cells reveals insights into mammary lineage establishment. Breast Cancer Res. 2011;13(4):R79.PubMedCrossRefGoogle Scholar
  10. 10.
    Dunbar ME, Young P, Zhang JP, McCaughern-Carucci J, Lanske B, Orloff JJ, et al. Stromal cells are critical targets in the regulation of mammary ductal morphogenesis by parathyroid hormone-related protein. Dev Biol. 1998;203(1):75–89.PubMedCrossRefGoogle Scholar
  11. 11.
    Dunbar ME, Dann PR, Robinson GW, Hennighausen L, Zhang JP, Wysolmerski JJ. Parathyroid hormone-related protein signaling is necessary for sexual dimorphism during embryonic mammary development. Development. 1999;126(16):3485–93.PubMedGoogle Scholar
  12. 12.
    Wysolmerski JJ, Philbrick WM, Dunbar ME, Lanske B, Kronenberg H, Broadus AE. Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development. Development. 1998;125(7):1285–94.PubMedGoogle Scholar
  13. 13.
    Cho YM, Woodard GL, Dunbar M, Gocken T, Jimenez JA, et al. Hair-cycle-dependent catagen transition. J Investig Dermatol. 2003;120(5):715–27.PubMedCrossRefGoogle Scholar
  14. 14.
    Cormier S, Delezoide AL, Silve C. Expression patterns of parathyroid hormone-related peptide (PTHrP) and parathyroid hormone receptor type 1 (PTHR1) during human development are suggestive of roles specific for each gene that are not mediated through the PTHrP/PTHR1 paracrine signaling pathway. Gene Expr Patterns. 2003;3(1):59–63.PubMedCrossRefGoogle Scholar
  15. 15.
    Wysolmerski JJ, Cormier S, Philbrick WM, Dann P, Zhang JP, Roume J, et al. Absence of functional type 1 parathyroid hormone (PTH)/PTH-related protein receptors in humans is associated with abnormal breast development and tooth impaction. J Clin Endocrinol Metab. 2001;86(4):1788–94.PubMedCrossRefGoogle Scholar
  16. 16.
    Voutilainen M, Lindfors PH, Lefebvre S, Ahtiainen L, Fliniaux I, Rysti E, et al. Ectodysplasin regulates hormone-independent mammary ductal morphogenesis via NF-kappaB. Proc Natl Acad Sci U S A. 2012;109:5744–9. United States.PubMedCrossRefGoogle Scholar
  17. 17.
    Hiremath M, Dann P, Fischer J, Butterworth D, Boras-Granic K, Hens J, et al. Parathyroid hormone-related protein activates Wnt signaling to specify the embryonic mammary mesenchyme. Development. 2012;139(22):4239–49.PubMedCrossRefGoogle Scholar
  18. 18.
    Wysolmerski JJ, Broadus AE, Zhou J, Fuchs E, Milstone LM, Philbrick WM. Overexpression of parathyroid hormone-related protein in the skin of transgenic mice interferes with hair follicle development. Proc Natl Acad Sci U S A. 1994;91(3):1133–7.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedGoogle Scholar
  20. 20.
    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.PubMedCrossRefGoogle Scholar
  21. 21.
    Heuberger B, Fitzka I, Wasner G, Kratochwil K. Induction of androgen receptor formation by epithelium-mesenchyme interaction in embryonic mouse mammary gland. Proc Natl Acad Sci U S A. 1982;79(9):2957–61.PubMedCrossRefGoogle Scholar
  22. 22.
    Hens J, Dann P, Hiremath M, Pan TC, Chodosh L, Wysolmerski J. Analysis of gene expression in PTHrP−/− mammary buds supports a role for BMP signaling and MMP2 in the initiation of ductal morphogenesis. Dev Dyn. 2009;238(11):2713–24.PubMedCrossRefGoogle Scholar
  23. 23.
    Sakakura T, Kusano I, Kusakabe M, Inaguma Y, Nishizuka Y. Biology of mammary fat pad in fetal mouse: capacity to support development of various fetal epithelia in vivo. Development. 1987;100(3):421–30.PubMedGoogle Scholar
  24. 24.
    Hoshino K. Development and function of mammary glands of mice prenatally exposed to testosterone propionate. Endocrinology. 1965;76:789–94.PubMedCrossRefGoogle Scholar
  25. 25.
    Neumann F, Berswordt-Wallrabe RVO, Elger W, Steinbeck H, Hahn JD, Kramer M. Aspects of androgen-dependent events as studied by antiandrogens. Recent Prog Horm Res. 1970;26:337–410.PubMedGoogle Scholar
  26. 26.
    Kratochwil K. Development and loss of androgen responsiveness in the embryonic rudiment of the mouse mammary gland. Dev Biol. 1977;61(2):358–65.PubMedCrossRefGoogle Scholar
  27. 27.
    Kratochwil K, Schwartz P. Tissue interaction in androgen response of embryonic mammary rudiment of mouse: identification of target tissue for testosterone. Proc Natl Acad Sci U S A. 1976;73(11):4041–4.PubMedCrossRefGoogle Scholar
  28. 28.
    Kratochwil K. In vitro analysis of the hormonal basis for the sexual dimorphism in the embryonic development of the mouse mammary gland. J Embryol Exp Morpholog. 1971;25(1):141–53.Google Scholar
  29. 29.
    Gondos B. Development and differentiation of the testis and male reproductive tract. In: Steinberger A, Steinberger B, editors. Testicular development, structure and function. New York: Raven; 1980. p. 3–20.Google Scholar
  30. 30.
    Mackie EJ, Chiquet-Ehrismann R, Pearson CA, Inaguma Y, Taya K, Kawarada Y, et al. Tenascin is a stromal marker for epithelial malignancy in the mammary gland. Proc Natl Acad Sci U S A. 1987;84(13):4621–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Dunbar ME, Wysolmerski JJ. Parathyroid hormone-related protein: a developmental regulatory molecule necessary for mammary gland development. J Mammary Gland Biol Neoplasia. 1999;4(1):21–34.PubMedCrossRefGoogle Scholar
  32. 32.
    Veltmaat JM, Mailleux AA, Thiery JP, Bellusci S. Mouse embryonic mammogenesis as a model for the molecular regulation of pattern formation. Differentiation. 2003;71(1):1–17.PubMedCrossRefGoogle Scholar
  33. 33.
    Toyoshima Y, Ohsako S, Nagano R, Matsumoto M, Hidaka S, Nishinakagawa H. Histological changes in mouse nipple tissue during the reproductive cycle. J Vet Med Sci. 1998;60(4):405–11.PubMedCrossRefGoogle Scholar
  34. 34.
    Montagna W. Histology and cytochemistry of human skin. XXXV. The nipple and areola. Br J Dermatol. 1970;83(Suppl):2–13.PubMedCrossRefGoogle Scholar
  35. 35.
    Inaguma Y, Kusakabe M, Mackie EJ, Pearson CA, Chiquet-Ehrismann R, Sakakura T. Epithelial induction of stromal tenascin in the mouse mammary gland: from embryogenesis to carcinogenesis. Dev Biol. 1988;128(2):245–55.PubMedCrossRefGoogle Scholar
  36. 36.
    Ghoussaini M, Fletcher O, Michailidou K, Turnbull C, Schmidt MK, Dicks E, et al. Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet. 2012;44(3):312–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Kremer R, Li J, Camirand A, Karaplis AC. Parathyroid hormone related protein (PTHrP) in tumor progression. Adv Exp Med Biol. 2011;720:145–60.PubMedCrossRefGoogle Scholar
  38. 38.
    Henderson MA, Danks JA, Slavin JL, Byrnes GB, Choong PF, Spillane JB, et al. Parathyroid hormone-related protein localization in breast cancers predict improved prognosis. Cancer Res. 2006;66(4):2250–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Henderson M, Danks J, Moseley J, Slavin J, Harris T, McKinlay M, et al. Parathyroid hormone-related protein production by breast cancers, improved survival, and reduced bone metastases. J Natl Cancer Inst. 2001;93(3):234–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Southby J, Kissin MW, Danks JA, Hayman JA, Moseley JM, Henderson MA, et al. Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer. Cancer Res. 1990;50(23):7710–6.PubMedGoogle Scholar
  41. 41.
    Powell GJ, Southby J, Danks JA, Stillwell RG, Hayman JA, Henderson MA, et al. Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res. 1991;51(11):3059–61.PubMedGoogle Scholar
  42. 42.
    Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6(1):1–6.PubMedGoogle Scholar
  43. 43.
    Garcia-Closas M, Couch FJ, Lindstrom S, Michailidou K, Schmidt MK, Brook MN, et al. Genome-wide association studies identify four ER negative-specific breast cancer risk loci. Nat Genet. 2013;45(4):392–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL, et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet. 2013;45(4):353–61.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.S-128 Department of Biological SciencesBoise State UniversityBoiseUSA
  2. 2.Department of Internal MedicineYale University School of MedicineNew HavenUSA

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