Skip to main content

Advertisement

SpringerLink
Log in

A mimic of phosphorylated prolactin inhibits human breast cancer cell proliferation via upregulation of p21 waf1

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

A mimic of phosphorylated prolactin (S179D PRL) inhibits mouse normal mammary HC11 cell proliferation through the upregulation of the vitamin D receptor (VDR) and p21. Here, we investigated whether S179D PRL also inhibited growth of human breast cancer MCF7 cells via VDR and p21. Western blots showed that S179D PRL upregulated VDR and p21 after the cells were incubated with S179D PRL for 3 days. These effects were blocked by the MAP kinase blocker PD98059 (25 μM), indicating that MAPK plays a role in VDR and p21 upregulation. To confirm whether VDR contributes to p21 upregulation, we used two constructs that express luciferase. One (p21 VDRE Luc) has the vitamin D response element (VDRE) in the p21 promoter region; the other (p21 NO-VDRE Luc) does not. The results show that S179D PRL upregulated p21 VDRE Luc activity in p21 VDRE Luc-transfected cells more than in p21 NO-VDRE-transfected cells, indicating that S179D PRL upregulated p21 via VDR. A cell proliferation assay showed that S179D PRL inhibits cell proliferation in a dose-dependent manner.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ueda EK, Soares CR, Bartolini P, DeGuzman A, Lorenson MY, Walker AM. A molecular mimic of phosphorylated prolactin (S179D PRL) secreted by eukaryotic cells has a conformation with an increased positive surface charge compared to that of unmodified prolactin. Biochemistry. 2009;48:6887–97.

    Article  CAS  PubMed  Google Scholar 

  2. Wu W, Coss D, Lorenson MY, Kuo CB, Xu X, Walker AM. Different biological effects of unmodified prolactin and a molecular mimic of phosphorylated prolactin involve different signaling pathways. Biochemistry. 2003;42:7561–70.

    Article  CAS  PubMed  Google Scholar 

  3. Kuo CB, Wu W, Xu X, Yang L, Chen C, Coss D, et al. Pseudophosphorylated prolactin (S179D PRL) inhibits growth and promotes beta-casein gene expression in the rat mammary gland. Cell Tissue Res. 2002;309:429–37.

    Article  CAS  PubMed  Google Scholar 

  4. Lee EJ, Moon GS, Choi WS, Kim WJ, Moon SK. Naringin-induced p21 waf1-mediated G (1)-phase cell cycle arrest via activation of the Ras/Raf/ERK signaling pathway in vascular smooth muscle cells. Food Chem Toxicol. 2008;46:3800–7.

    Article  CAS  PubMed  Google Scholar 

  5. Luo Y, Hurwitz J, Massague J. Cell cycle inhibition by independent CDK and PCNA binding domains in p21 Cip1. Nature. 1995;375:159–61.

    Article  CAS  PubMed  Google Scholar 

  6. Wu W, Chen YH, Ueda E, Tan DY, Bartolini P, Walker AM. Different forms of prolactin have opposing effects on the expression of cell cycle regulatory proteins in differentiated mammary epithelial cells. Oncol Res. 2006;16:75–84.

    CAS  PubMed  Google Scholar 

  7. Wang Q, Lee D, Chandraratna RAS, Sysounthone V, Christakos S, Korah R, et al. 1,25-Dihydroxyvitamin D3 and retinoic acid analogues induce differentiation in breast cancer cells with function-and cell- specific additive effects. Breast Cancer Res Treat. 2001;67:157–68.

    Article  CAS  PubMed  Google Scholar 

  8. Colston KW, Hansen CM. Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer. Endocr Relat Cancer. 2002;9:45–59.

    Article  CAS  PubMed  Google Scholar 

  9. Chouvet C, Berger U, Coombes R. 1,25-Dihydroxyvitamin, D3 inhibitory effect on the growth of two human breast cancer cell lines (MCF7, BT-20). J Steroid Biochem. 1986;24:373–6.

    Article  CAS  PubMed  Google Scholar 

  10. Jensen SS, Madsen MW, Lukas J, Bartek J, Binderup L. Sensitivity to growth suppression by 1alpha, 25-dihydroxyvitamin D(3) among MCF-7 clones correlates with vitamin D receptor protein induction. J Steroid Biochem Mol Biol. 2002;81:123–33.

    Article  CAS  PubMed  Google Scholar 

  11. Gaschott T, Wachtershauser A, Steinhiber D, Stein J. 1,25-Dihydroxycholecalciferol enhances butyrate-induced p21(Waf1/Cip1) expression. Biochem Biophys Res Commun. 2001;283:80–5.

    Article  CAS  PubMed  Google Scholar 

  12. Liu M, Lee MH, Cohen M, Bommakanti M, Freeman LP. Transcriptional activation of the cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. Genes Dev. 1996;10:142–53.

    Article  CAS  PubMed  Google Scholar 

  13. Wang Q, Lee D, Sysounthone V, Chandraratna RAS, Christakos S, Korah R, et al. 1,25-Dihydroxyvitamin D3 and retinoic acid analogues induce differentiation in breast cancer cells with function-and cell-specific additive effects. Breast Cancer Res Treat. 2001;67:157–68.

    Article  CAS  PubMed  Google Scholar 

  14. Colston KW, Hansen CM. Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer. Endocr-Relat. Cancer. 2002;9:45–59.

    Article  CAS  PubMed  Google Scholar 

  15. Buras RR, Schumaker LM, Davoodi F, Brenner RV, Shabahang M, Nauta RJ, et al. Vitamin D receptors in breast cancer cells. Breast Cancer Res Treat. 1994;31:191–202.

    Article  CAS  PubMed  Google Scholar 

  16. Mezzetti G, Barbiroli B, Oka T. 1,25-Dihydroxycholecalciferol receptor regulation in hormonally induced differentiation of mouse mammary gland in culture. Endocrinology. 1987;120:2488–93.

    Article  CAS  PubMed  Google Scholar 

  17. Colston K, Berger U, Wilson P, Hadcocks L, Naeem I, Earl H, et al. Mammary gland 1,25-dihydroxyvitamin D3 receptor content during pregnancy and lactation. Mol Cell Endocrinol. 1988;60:15–22.

    Article  CAS  PubMed  Google Scholar 

  18. Chen TJ, Kuo CB, Tsai KF, Liu JW, Chen DY, Walker AM. Development of recombinant human prolactin receptor antagonists by molecular mimicry of the phosphorylated hormone. Endocrinology. 1998;139:609–16.

    Article  CAS  PubMed  Google Scholar 

  19. Schroeder MD, Brockman JL, Walker AM, Schuler LA. Inhibition of prolactin (PRL)-induced proliferative signals in breast cancer cells by a molecular mimic of phosphorylated PRL, S179D-PRL. Endocrinology. 2003;144:5300–7.

    Article  CAS  PubMed  Google Scholar 

  20. Davis D, Pintucci G, Stern A. MAPK-dependent expression of p21 waf1 and p27 kip1 in PMA-induced differentiation of HL60 cells. FEBS Lett. 2000;472:50–2.

    Article  Google Scholar 

  21. Liu Y, Martindale JL, Gorospe M, Holbrook NJ. Regulation of p21 waf1/cip1 expression through mitogen-activated protein kinase signaling pathway. Cancer Res. 1996;56:31–5.

    CAS  PubMed  Google Scholar 

  22. Lessor T, Yoo JY, Hamburger AW. Regulation of heregulin beta-1-induced differentiation in a human breast carcinoma cell line by the extracellular-regulated kinase (ERK) pathway. J Cell Biochem. 1998;70:587–95.

    Article  CAS  PubMed  Google Scholar 

  23. Ho TC, Chen SL, Yang YC, Chen CY, Feng FP, Hsieh JW, et al. 15-Deoxy-delta 12,14-prostaglandin J2 induces vascular endothelial cell apoptosis through the sequential activation of MAPS and p53. J Biol Chem. 2008;283:30273–88.

    Article  CAS  PubMed  Google Scholar 

  24. Chin YE, Kitagawa M, Su WC, You ZH, Iwamoto Y, Fu XY. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 waf1/cip1 mediated by STAT1. Science. 1996;272:719–22.

    Article  CAS  PubMed  Google Scholar 

  25. Wyszomierski SL, Yeh J, Rosen JM. Glucocorticoid receptor/signal transducer and activator transcription 5 (STAT5) interactions enhances STAT5 activation by prolong STAT5 DNA binding and tyrosine phosphorylation. Mol Endocrinol. 1999;13:330–43.

    Article  CAS  PubMed  Google Scholar 

  26. Barsony J, Pike JW, DeLuca HF, Marx SJ. Immunocytology with microwave-fixed fibroblasts shows 1 alpha, 25-dihydroxyvitamin D3-dependent rapid and estrogen-dependent slow reorganization of vitamin D receptors. Cell Biol. 1990;111:2385–95.

    Article  CAS  Google Scholar 

  27. Wu W, Ginsburg E, Vonderhaar BK, Walker AM. S179D prolactn increases vitamin D receptor and p21 through up-regulation of short 1b prolactin receptor in human prostate cancer cells. Cancer Res. 2005;65:7509–15.

    Article  CAS  PubMed  Google Scholar 

  28. Huang KT, Walker AM. Long term increased expression of the short form 1b prolactin receptor in PC3 human prostate cancer cells decreases cell growth and migration, and causes multiple changes in gene expression consistent with reduced invasive capacity. Prostate. 2009;8:37–47.

    Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr. Ameae Walker (University of California, Riverside) for her support in experiments. This work was supported by the Science and Development Plan of the Beijing Education Committee (KM200910025008). The authors would also like to thank Dr. Leopard Freeman (Memorial Sloan-Kettering Cancer Center) for his generosity in providing constructs.

Author information

Authors and Affiliations

  1. Biology Research Institute of the United Laboratories International Holdings Limited, 528467, Zhuhai, China

    Wenjie Xie

  2. School of Public Health and Family Medicine, Capital Medical University, 100069, Beijing, China

    Yan He, Da Huo, Yafang Huang & Wei Wu

Authors
  1. Wenjie Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Da Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yafang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei Wu.

Additional information

Wenjie Xie and Yan He contributed to this work equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xie, W., He, Y., Huo, D. et al. A mimic of phosphorylated prolactin inhibits human breast cancer cell proliferation via upregulation of p21 waf1. Med Oncol 27, 1340–1345 (2010). https://doi.org/10.1007/s12032-009-9386-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-009-9386-6

Keywords

Search

Navigation