Skip to main content

Advertisement

SpringerLink
Log in

Progesterone stimulates proliferation of a long-lived epithelial cell population in rat mammary gland

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Background: Long-lived somatic cells such as stem/progenitor cells may progressively accumulate oncogenic mutations and cause cancer. Some evidence suggests that pre-menopausal administration of progesterone confers a long-term increased risk of breast cancer. Aim: To clarify the effect of progesterone on long-lived mammary epithelial cells in rats. Materials and methods: Female Sprague-Dawley rats (3 and 7 weeks of age) were implanted sc with 14-day slow-release pellets of 5-bromo-2′-deoxyuridine (BrdU) and were sacrificed every 2 weeks between 0 and 10 weeks after the release period. Some rats at 7 weeks of age were also implanted with progesterone and sacrificed 0 or 10 weeks after the release period. Mammary glands were examined by immunohistochemistry and immunofluorescence for BrdU, proliferative cell nuclear antigen (PCNA) and progesterone receptor (PR). Results: After BrdU labeling of 3- and 7-week-old rats, the BrdU index decreased gradually over 10 weeks and resulted in small fractions (1–3%) of label-retaining epithelial cells (LREC) 10 weeks after BrdU labeling in both mammary lobules and ducts. Treatment with progesterone during labeling significantly increased the fraction of long-lived LREC in lobules and ducts by 9- and 4-fold, respectively. The long-lived LREC population in the ducts was enriched for PCNA- and PR-positive cells, but the percentage of positive cells was not affected by progesterone in either lobules or ducts. Conclusions: Progesterone stimulates proliferation of a long-lived epithelial cell population in the mammary lobules and ducts of rats. Such cells in the duct are characterized by a high proliferation rate and PR expression.

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

Similar content being viewed by others

References

  1. Visvader JE. Cells of origin in cancer. Nature 2011, 469: 314–22.

    Article  PubMed  Google Scholar 

  2. Booth BW, Smith GH. Estrogen receptor-alpha and progesterone receptor are expressed in label-retaining mammary epithelial cells that divide asymmetrically and retain their template DNA strands. Breast Cancer Res 2006, 8: R49.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Smith GH. Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands. Development 2005, 132: 681–7.

    Article  PubMed  Google Scholar 

  4. Fernandez-Gonzalez R, Illa-Bochaca I, Welm BE, et al. Mapping mammary gland architecture using multi-scale in situ analysis. Integr Biol (Camb) 2009, 1: 80–9.

    Article  Google Scholar 

  5. Welm BE, Tepera SB, Venezia T, Graubert TA, Rosen JM, Goodell MA. Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol 2002, 245: 42–56.

    Article  PubMed  Google Scholar 

  6. Asselin-Labat ML, Sutherland KD, Barker H, et al. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol 2007, 9: 201–9.

    Article  PubMed  Google Scholar 

  7. Shackleton M, Vaillant F, Simpson KJ, et al. Generation of a functional mammary gland from a single stem cell. Nature 2006, 439: 84–8.

    Article  PubMed  Google Scholar 

  8. Stingl J, Eirew P, Ricketson I, et al. Purification and unique properties of mammary epithelial stem cells. Nature 2006, 439: 993–7.

    PubMed  Google Scholar 

  9. Anderson E. The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Res 2002, 4: 197–201.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Beleut M, Rajaram RD, Caikovski M, et al. Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc Natl Acad Sci U S A 2010, 107: 2989–94.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Asselin-Labat ML, Vaillant F, Sheridan JM, et al. Control of mammary stem cell function by steroid hormone signalling. Nature 2010, 465: 798–802.

    Article  PubMed  Google Scholar 

  12. Joshi PA, Jackson HW, Beristain AG, et al. Progesterone induces adult mammary stem cell expansion. Nature 2010, 465: 803–7.

    Article  PubMed  Google Scholar 

  13. Colditz GA. Estrogen, estrogen plus progestin therapy, and risk of breast cancer. Clin Cancer Res 2005, 11: 909s–17s.

    PubMed  Google Scholar 

  14. Horwitz KB. The Year in Basic Science: update of estrogen plus progestin therapy for menopausal hormone replacement implicating stem cells in the increased breast cancer risk. Mol Endocrinol 2008, 22: 2743–50.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Cirpan T, Iscan O, Terek MC, et al. Proliferative effects of different hormone regimens on mammary glands in ovariectomized rats. Eur J Gynaecol Oncol 2006, 27: 256–61.

    PubMed  Google Scholar 

  16. Fabre A, Fournier A, Mesrine S, et al. Oral progestagens before menopause and breast cancer risk. Br J Cancer 2007, 96: 841–4.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Fabre A, Fournier A, Mesrine S, et al. Progestagens use before menopause and breast cancer risk according to histology and hormone receptors. Cancer Epidemiol Biomarkers Prev 2008, 17: 2723–8.

    Article  PubMed  Google Scholar 

  18. Aldaz CM, Liao QY, LaBate M, Johnston DA. Medroxyprogesterone acetate accelerates the development and increases the incidence of mouse mammary tumors induced by dimethylbenzanthracene. Carcinogenesis 1996, 17: 2069–72.

    Article  PubMed  Google Scholar 

  19. Gould MN. Rodent models for the study of etiology, prevention and treatment of breast cancer. Semin Cancer Biol 1995, 6: 147–52.

    Article  PubMed  Google Scholar 

  20. Medina D, Thompson HJ. A comparison of the salient features of mouse, rat, and human mammary tumorigenesis. In: Ip MM, Asch BB, eds. Methods in Mammary Gland Biology and Breast Cancer Research. New York: Kluwer Academic/Plenum Publishers. 2000, 31–6.

    Chapter  Google Scholar 

  21. Nandi S, Guzman RC, Yang J. Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis. Proc Natl Acad Sci U S A 1995, 92: 3650–7.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Imaoka T, Nishimura M, Iizuka D, et al. Radiation-induced mammary carcinogenesis in rodent models: what’s different from chemical carcinogenesis? J Radiat Res (Tokyo) 2009, 50: 281–93.

    Article  Google Scholar 

  23. Russo J, Wilgus G, Russo IH. Susceptibility of the mammary gland to carcinogenesis: I Differentiation of the mammary gland as determinant of tumor incidence and type of lesion. Am J Pathol 1979, 96: 721–36.

    PubMed Central  PubMed  Google Scholar 

  24. Clifton KH. Thyroid and mammary radiobiology: radiogenic damage to glandular tissue. Br J Cancer Suppl 1986, 7: 237–50.

    PubMed Central  PubMed  Google Scholar 

  25. Kamiya K, Clifton KH, Gould MN, Yokoro K. Control of ductal vs. alveolar differentiation of mammary clonogens and susceptibility to radiation-induced mammary cancer. J Radiat Res 1991, 32(Suppl 2): 181–94.

    Article  PubMed  Google Scholar 

  26. Gould MN, Biel WF, Clifton KH. Morphological and quantitative studies of gland formation from inocula of monodispersed rat mammary cells. Exp Cell Res 1977, 107: 405–16.

    Article  PubMed  Google Scholar 

  27. Storment JM, Meyer M, Osol G. Estrogen augments the vasodilatory effects of vascular endothelial growth factor in the uterine circulation of the rat. Am J Obstet Gynecol 2000, 183: 449–53.

    Article  PubMed  Google Scholar 

  28. Freeman ML, Saed GM, Diamond MP. Hormone-independent ovarian influence on adhesion development. Fertil Steril 2002, 78: 340–6.

    Article  PubMed  Google Scholar 

  29. Potten CS, Hume WJ, Reid P, Cairns J. The segregation of DNA in epithelial stem cells. Cell 1978, 15: 899–906.

    Article  PubMed  Google Scholar 

  30. Asselin-Labat ML, Shackleton M, Stingl J, et al. Steroid hormone receptor status of mouse mammary stem cells. J Natl Cancer Inst 2006, 98: 1011–4.

    Article  PubMed  Google Scholar 

  31. Sleeman KE, Kendrick H, Robertson D, Isacke CM, Ashworth A, Smalley MJ. Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. J Cell Biol 2007, 176: 19–26.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Chepko G, Smith GH. Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal. Tissue Cell 1997, 29: 239–53.

    Article  PubMed  Google Scholar 

  33. Clarke RB. Steroid receptors and proliferation in the human breast. Steroids 2003, 68: 789–94.

    Article  PubMed  Google Scholar 

  34. Graham JD, Mote PA, Salagame U, et al. DNA replication licensing and progenitor numbers are increased by progesterone in normal human breast. Endocrinology 2009, 150: 3318–26.

    Article  PubMed Central  PubMed  Google Scholar 

  35. 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: 211–25.

    Article  PubMed  Google Scholar 

  36. Smith GH. Experimental mammary epithelial morphogenesis in an in vivo model: evidence for distinct cellular progenitors of the ductal and lobular phenotype. Breast Cancer Res Treat 1996, 39: 21–31.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Radiobiology for Children’s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan

    T. Imaoka PhD, H. Hisatsune, Y. Sakanishi, Y. Nishimura, M. Nishimura & Y. Shimada

  2. Tokyo College of Medico-Pharmaco Technology, Tokyo, Japan

    H. Hisatsune & Y. Sakanishi

  3. Tokyo Business Service Co. Ltd., Tokyo, Japan

    Y. Nishimura

  4. Department of Nanobiology, Graduate School of Advanced Integration Science, Chiba University, Chiba, Japan

    Y. Shimada

Authors
  1. T. Imaoka PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Hisatsune
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y. Sakanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y. Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y. Shimada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T. Imaoka PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Imaoka, T., Hisatsune, H., Sakanishi, Y. et al. Progesterone stimulates proliferation of a long-lived epithelial cell population in rat mammary gland. J Endocrinol Invest 35, 828–834 (2012). https://doi.org/10.3275/8189

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.3275/8189

Key-words

Search

Navigation