Summary
Two recent papers demonstrate that prolactin plays an important role in the induction and progression of mammary tumours. Retinoids have been shown to be potent inhibitors of breast carcinogenesis. We studied expression of prolactin receptor mRNA in human breast cancer cell lines MCF-7, SKBR-3, T47D and BT-20 treated with and without retinoids using Northern blot and a quantitative polymerase chain reaction (PCR) method. In all cell lines, all-trans- and 9-cis-retinoic acid, as well as the retinoic acid receptor γ (RAR-γ) selective agonists CD2325 and CD437 (1 μM), were able to down-regulate prolactin receptor. After 1 h, a significant reduction was detectable and maximal effect was achieved after 24 h of treatment. Pretreatment with retinoic acid also reduced the prolactin-/prolactin receptor-dependent signal transduction and activation of transcription 5 (STAT-5) activation in T47D cells. Cycloheximide failed to abrogate the retinoic acid-induced decline in prolactin receptor mRNA levels, indicating that this effect was not dependent upon continuing protein synthesis. Similarly, no change in the stability of prolactin receptor mRNA was observed during 12 h of retinoic acid treatment. In conclusion, our results demonstrate that retinoids are able to inhibit the expression of prolactin receptor message, which encodes an important growth factor receptor in breast cancer cells. This action could be responsible for the anti-tumour effects of retinoids.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Anderson, E., Ferguson, J. E., Morten, H., Shalet, S. M., Robinson, E. & Howell, A. (1993). Serum immunoreactive and bioactive lactogenic hormones in advanced breast cancer patients treated with bromocriptine and octreotide. Eur J Cancer 29: 209–217.
Anzano, M. A., Byers, S. W., Smith, J. M., Peer, C. W., Mullen, L. T., Brown, C. C., Roberts, A. B. & Sporn, M. B. (1994). Prevention of breast cancer in the rat with 9-cis retinoic acid as a single agent and in combination with tamoxifen. Cancer Res 54: 4614–4617.
Bhatavdekar, J. N. & Patel, D. D. (1997). Ectopic prolactin: as a local growth promoter in breast cancer (abstract). In Proceedings of 33rd Annual Meeting of the American Society of Clinical Oncology, (1990). Vol. 16: ASCO
Biswas, R. & Vonderhaar, B. K. (1987). Role of serum in prolactin responsiveness of MCF-7 human breast cancer cells in long term tissue culture. Cancer Res 47: 3509–3514.
Bonneterre, J., Peyrat, J. P., Beuscart, R., Lefebvre, J. & Demaille, A. (1987). Prognostic significance of prolactin receptors in human breast cancer. Cancer Res 47: 4724–4728.
Boutin, J. M., Edery, M., Shirota, M., Jolicoeur, C., Lesueur, L., Ali, S., Gould, D., Djiane, J. & Kelly, P. (1989). Identification of a cDNA encoding a long form of prolactin receptor in human hepatoma and breast cancer cells. Mol Endocrinol 3: 1455–1461.
Clevenger, C. V., Chang, W-P, Ngo, W., Pasha, T. L. M., Montone, K. T. & Tomaszewski, J. E. (1995). Expression of prolactin and prolactin receptor in human breast carcinoma. Am J Pathol 146: 695–705.
Cobleigh, M. A., Dowlashahi, K., Deutsch, T. A., Mehta, R. G., Moon, R. C., Minn, F., Benson, A. B., Rademaker, A. W., Ashenhurst, J. B., Wade, J. L. & Wolter, J. (1993). Phase I/II trial of tamoxifen with or without fenretinide, an analog of vitamin A, in women with metastatic breast cancer. J Clin Oncol 11: 474–477.
Costa, A. (1993). Breast cancer chemoprevention. Eur J Cancer 29A: 589–592.
Costa, A., Formelli, F., Chiesa, F., Decensi, A., De Palo, G. & Veronesi, U. (1994). Prospects of chemoprevention of human cancer with the synthetic retinoid fenretinide. Cancer Res 54 (suppl.): 2032S–2037S.
Doppler, W. (1994). Regulation of gene expression by prolactin. Rev Physiol Biochem Pharmacol 124: 92–130.
Doppler, W., Villunger, A., Jennewein, P., Brduscha, K., Groner, B. & Ball, R. K. (1991). Lactogenic hormone and cell type specific control of the whey acidic protein gene promoter in transfected mouse cells. Mol Endocrinol 5: 1624–1632.
Fanjul, A. N., Bouterfa, H., Dawson, M. & Pfahl, M. (1996). Potential role for retinoic acid receptor-γ in the inhibition of breast cancer cells by selective retinoids and interferons. Cancer Res 56: 1571–1577.
Formelli, F., Clerici, M., Campa, T., Gaetana Di Mauro, M., Magni, A., Mascotti, G., Moglia, D., De Palo, G., Costa, A. & Veronesi, U. (1993). Five year administration of fenretinide: pharmacokinetics and effects on plasma retinol concentrations. J Clin Oncol 11: 2036–2042.
Ginsburg, E. & Vonderhaar, B. K. (1995). Prolactin synthesis and secretion by human breast cancer cells. Cancer Res 55: 2591–2595.
Goffin, V. & Kelly, P. A. (1996). Prolactin and growth hormone receptors. Clin Endocrinol 45: 247–255.
Gottardis, M. M., Lamph, W. W., Shalinsky, D. R., Wellstein, A. & Heyman, R. A. (1996). The efficacy of 9-cis retinoic acid in experimental model of cancer. Breast Cancer Res Treatment 38: 85–96.
Gouilleux, F., Wakao, H., Mundt, M. & Groner, B. (1994). Prolactin induces phosphorylation of tyr694 of Stat5(MGF), a prerequisite for DNA binding and induction of transcription. EMBO J 13: 4361–4368.
Koga, M. & Sutherland, R. L. (1991). Retinoic acid acts synergistically with 1,25-dihydroxyvitamin D3 or antiestrogen to inhibit human breast cancer cell proliferation. J Steroid Biochem Mol Biol 39: 455–460.
Malarkey, W. B., Kennedy, M., Allred, L. E. & Milo, G. (1983). Physiological concentrations of prolactin can promote the growth of human breast tumor cells in culture. J Clin Endocrinol Metab 56: 673–677.
Marth, C., Daxenbichler, G. & Dapunt, O. (1986). Synergistic antiproliferative effect of human recombinant interferons and retinoic acid in cultured breast cancer cells. J Natl Cancer Inst 77: 1197–1202.
Marth, C., Widschwendter, M. & Daxenbichler, G. (1993). Mechanism of synergistic action of all-trans- or 9-cis-retinoic acid and interferons in breast cancer cells. J Steroid Biochem Mol Biol 47: 123–126.
Møldrup, A., Ormandy, C., Nagano, M., Murthy, K., Banville, D., Tronche, F. & Kelly, P. A. (1996). Differential promoter usage in prolactin receptor gene expression: hepatocyte nuclear factor 4 binds to and activates the promoter preferentially active in the liver. Mol Endocrinol 10: 661–671.
Moon, R. C. & Mehta, R. G. (1990). Chemoprevention of mammary cancer by retinoids. Basic Life Sci 52: 213–224.
Ng, S. T., Zhou, J., Adesanya, O. O., Wang, J., LeRoith, D. & Bondy, C. A. (1997). Growth hormone treatment induces mammary gland hyperplasia in aging primates. Nature Med 3: 1141–1144.
Ormandy, C. J., de Fazio, A., Kelly, P. A. & Sutherland, R. L. (1992). Transcriptional regulation of prolactin receptor gene expression by sodium butyrate in MCF-7 human breast cancer cells. Endocrinology 131: 982–984.
Ormandy, C. J., Lee, C. S. L., Kelly, P. A. & Sutherland, R. (1993). Regulation of prolactin receptor expression by the tumour promoting phorbol ester 12-o-tetradecanoylphorbol-13-acetate in human breast cancer cells. J Cell Biochem 52: 47–56.
Rui, H., Kirken, R. A. & Farrar, W. L. (1994). Activation of receptor-associated tyrosine kinase JAK2 by prolactin. J Biol Chem 269: 5364–5368.
Sachs, L. (1992). Angewandte Statistik, pp. 380–392, Springer-Verlag: Berlin
Shao, Z-M, Dawson, M. I., Su Li, X., Rishi, A. K., Sheikh, M. S., Han, Q-X, Ordonez, J. V., Shroot, B. & Fontana, J. A. (1995). p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. Oncogene 11: 493–504.
Shaw-Bruha, C. M., Pirrucello, S. J. & Shull, J. D. (1997). Expression of the prolactin gene in normal and neoplastic human breast tissues and human mammary cell lines: promoter usage and alternative mRNA splicing. Breast Cancer Res Treatment 44: 243–253.
Sporn, M. B., Roberts, A. B. & Goodman, D. S. (1994). The Retinoids: Biology, Chemistry and Medicine, 2nd edn. Raven Press: New York
Tso, J. H., Sun, X-H, Kao, T., Reece, K. S. & Wu, R. (1985). Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase c-DNA: genomic complexity and molecular evolution of the gene. Nucl Acids Res 13: 2485–2502.
Vonderhaar, B. K. (1989). Estrogens are not required for prolactin induced growth of MCF-7 human breast cancer cells. Cancer Lett 47: 105–110.
Welsch, C. W. & Nagasawa, H. (1997). Prolactin and murine tumorigenesis: a review. Cancer Res 37: 951–963.
Welsch, C. W., DeHoog, J. V., Scieszka, K. M. & Aylsworth, C. F. (1984). Retinoid feeding, hormone inhibition, and/or immune stimulation and the progression of N-methyl-N-nitrosourea-induced rat mammary carcinoma: suppression by retinoids of peptide hormone-induced tumor cell proliferation in vivo and in vitro. Cancer Res 44: 166–171.
Welte, T., Garimorth, K., Philipp, S. & Doppler, W. (1994). Prolactin-dependent activation of a tyrosine phosphorylated DNA binding factor in mouse mammary epithelial cells. Mol Endocrinol 8: 1091–1102.
Wennbo, H., Gebre-Medhin, M., Gritli-Linde, A., Ohlsson, C., Isaksson, O. G. P. & Törnell, J. (1997). Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice. J Clin Invest 100: 2744–2751.
Widschwendter, M., Daxenbichler, G., Dapunt, O. & Marth, C. (1995). Effects of retinoic acid and interferon-γ on expression of retinoic acid receptor and cellular retinoic acid binding protein in breast cancer cells. Cancer Res 55: 2135–2139.
Widschwendter, M., Daxenbichler, G., Bachmair, F., Müller, E., Zeimet, A. G., Windbichler, G., Uhl-Steidl, M., Lang, T. & Marth, C. (1996). Interaction of retinoic acid and interferon-α in breast cancer cell lines. Anticancer Res 16: 369–374.
Widschwendter, M., Daxenbichler, G., Culig, Z., Michel, S., Zeimet, A. G., Mörtl, M. G., Widschwendter, A. & Marth, C. (1997). Activity of retinoic acid receptor-γ selectively binding retinoids alone and in combination with interferon-γ in breast cancer cell lines. Int J Cancer 71: 497–504.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Widschwendter, M., Widschwendter, A., Welte, T. et al. Retinoic acid modulates prolactin receptor expression and prolactin-induced STAT-5 activation in breast cancer cells in vitro. Br J Cancer 79, 204–210 (1999). https://doi.org/10.1038/sj.bjc.6690034
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690034
Keywords
This article is cited by
-
Regulation of Prolactin Receptor Levels and Activity in Breast Cancer
Journal of Mammary Gland Biology and Neoplasia (2008)