Expression of ErbB receptors in the pre-pubertal and pubertal virgin mammary glands of dairy cows

  • Received : 2012.11.16
  • Accepted : 2012.11.26
  • Published : 2012.12.31


In the present study, we investigated the expression patterns of ErbB family proteins in the pre-pubertal and pubertal mammary glands of dairy cows in association with gland development. For this study, we performed immunohistochemistry for ErbB-1-4 and Ki-67 cell proliferation marker. We found that the pre-pubertal and pubertal mammary glands had typical structures, including ducts and terminal end buds embedded in the stroma, and no development of lobuloalveolar structures. On immunohistochemistry, ErbB-2 and ErbB-3 were strongly expressed in the cytoplasm and nuclei in the epithelial cells of mammary ducts and terminal end buds, and stromal cells, whereas ErbB-1 and ErbB-4 were weakly expressed only in the cytoplasm of gland epithelium and stromal cells, irrespective of the developmental stage. Cell proliferation was inactive in the mammary gland cell compartments in both phases. Thus, expression of the ErbB family in the developing mammary glands was not associated with their functional effects, such as cell proliferation and lobuloalveolar development. In conclusion, ErbB receptors were differentially expressed in the epithelial and stromal cells of virgin mammary glands of dairy cows. Compared with rodent mammary glands, ErbB-3 and ErbB-4 were found to be highly expressed in bovine mammary glands.


Supported by : Rural Development Administration


  1. Anderson E. The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Res 2002, 4, 197-201.
  2. Anido J, Scaltriti M, Bech Serra JJ, Santiago Josefat B, Todo FR, Baselga J, Arribas J. Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation. EMBO J 2006, 25, 3234-3244.
  3. Chen X, Levkowitz G, Tzahar E, Karunagaran D, Lavi S, Ben-Baruch N, Leitner O, Ratzkin BJ, Bacus SS, Yarden Y. An immunological approach reveals biological differences between the two NDF/heregulin receptors, ErbB- 3 and ErbB-4. J Biol Chem 1996, 271, 7620-7629.
  4. Convey EM. Serum hormone concentrations in ruminants during mammary growth, lactogenesis, and lactation: a review. J Dairy Sci 1974, 57, 905-917.
  5. Darcy KM, Zangani D, Wohlhueter AL, Huang RY, Vaughan MM, Russell JA, Ip MM. Changes in ErbB2 (her-2/neu), ErbB3, and ErbB4 during growth, differentiation, and apoptosis of normal rat mammary epithelial cells. J Histochem Cytochem 2000, 48, 63-80.
  6. Heldin CH. Dimerization of cell surface receptors in signal transduction. Cell 1995, 80, 213-223.
  7. Jackson-Fisher AJ, Bellinger G, Breindel JL, Tavassoli FA, Booth CJ, Duong JK, Stern DF. ErbB3 is required for ductal morphogenesis in the mouse mammary gland. Breast Cancer Res 2008, 10, R96.
  8. Jackson-Fisher AJ, Bellinger G, Ramabhadran R, Morris JK, Lee KF, Stern DF. ErbB2 is required for ductal morphogenesis of the mammary gland. Proc Natl Acad Sci U S A 2004, 101, 17138-17143.
  9. Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 2003, 284, 31-53.
  10. Knight CH. The importance of cell division in udder development and lactation. Livest Prod Sci 2000, 66, 169-176.
  11. Mallepell S, Krust A, Chambon P, Brisken C. Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci U S A 2006, 103, 2196-2201.
  12. McNally S, Martin F. Molecular regulators of pubertal mammary gland development. Ann Med 2011, 43, 212-234.
  13. Mukku VR, Stancel GM. Regulation of epidermal growth factor receptor by estrogen. J Biol Chem 1985, 260, 9820- 9824.
  14. Muraoka-Cook RS, Feng SM, Strunk KE, Earp HS 3rd. ErbB4/HER4: role in mammary gland development, differentiation and growth inhibition. J Mammary Gland Biol Neoplasia 2008, 13, 235-246.
  15. Offterdinger M, Schofer C, Weipoltshammer K, Grunt TW. c-erbB-3: a nuclear protein in mammary epithelial cells. J Cell Biol 2002, 157, 929-939.
  16. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000, 19, 3159-3167.
  17. Riese DJ 2nd, Stern DF. Specificity within the EGF family/ErbB receptor family signaling network. Bioessays 1998, 20, 41-48.<41::AID-BIES7>3.0.CO;2-V
  18. 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, 305-317.
  19. Schroeder JA, Lee DC. Dynamic expression and activation of ERBB receptors in the developing mouse mammary gland. Cell Growth Differ 1998, 9, 451-464.
  20. Sheffield LG. Hormonal regulation of epidermal growth factor receptor content and signaling in bovine mammary tissue. Endocrinology 1998, 139, 4568-4575.
  21. Spitzer E, Grosse R. EGF receptors on plasma membranes purified from bovine mammary gland of lactating and pregnant animals. Biochem Int 1987, 14, 581-588.
  22. Stern DF. ErbBs in mammary development. Exp Cell Res 2003, 284, 89-98.
  23. Sternlicht MD, Sunnarborg SW, Kouros-Mehr H, Yu Y, Lee DC, Werb Z. Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17- dependent shedding of epithelial amphiregulin. Development 2005, 132, 3923-3933.
  24. Wang SC, Lien HC, Xia W, Chen IF, Lo HW, Wang Z, Ali-Seyed M, Lee DF, Bartholomeusz G, Ou-Yang F, Giri DK, Hung MC. Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell 2004, 6, 251-261.
  25. Welsch CW, McManus MJ, DeHoog JV, Goodman GT, Tucker HA. Hormone-induced growth and lactogensis of grafts of bovine mammary gland maintained in the athymic "nude" mouse. Cancer Res 1979, 39 (6 Pt 1), 2046-2050.
  26. Xie W, Paterson AJ, Chin E, Nabell LM, Kudlow JE. Targeted expression of a dominant negative epidermal growth factor receptor in the mammary gland of transgenic mice inhibits pubertal mammary duct development. Mol Endocrinol 1997, 11, 1766-1781.
  27. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001, 2, 127-137.