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. 1984 Oct 1;99(4):1410–1415. doi: 10.1083/jcb.99.4.1410

Progression to steroid autonomy in S115 mouse mammary tumor cells: role of DNA methylation

PMCID: PMC2113315  PMID: 6090471

Abstract

Although monoclonal in origin, mammary tumors acquire a marked heterogeneity of cell phenotypes, including a mixture of steroid hormone-sensitive cells and insensitive cells. We describe here long- term studies on the effects of androgen withdrawal on cloned androgen- responsive S115 mouse mammary tumor cells as a model system to investigate mechanisms by which tumor cells lose their steroid sensitivity. In the prolonged absence of androgen, the cells lost hormone-sensitive parameters reproducibly, including loss of proliferative response, saturation density response, cell morphology response, and mouse mammary tumor virus long terminal repeat (MMTV-LTR)- related RNA. These experiments have demonstrated that when deprived of hormone in the long term, a clone of responsive cells gives rise reproducibly to a population of unresponsive cells in an ordered series of phenotypic changes. At the time when the cells lost all androgen response in terms of cell biology and MMTV-LTR-RNA, increased methylation of MMTV-LTR sequences in the DNA was detected. Thereafter recovery of androgen sensitivity has not been achieved in any of these parameters. The possible role of de novo DNA methylation in the progression to androgen autonomy of S115 cells is discussed.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bird A. P. DNA methylation--how important in gene control? Nature. 1984 Feb 9;307(5951):503–504. doi: 10.1038/307503a0. [DOI] [PubMed] [Google Scholar]
  2. Breznik T., Cohen J. C. Altered methylation of endogenous viral promoter sequences during mammary carcinogenesis. Nature. 1982 Jan 21;295(5846):255–257. doi: 10.1038/295255a0. [DOI] [PubMed] [Google Scholar]
  3. Cohen J. C. Methylation of milk-borne and genetically transmitted mouse mammary tumor virus proviral DNA. Cell. 1980 Mar;19(3):653–662. doi: 10.1016/s0092-8674(80)80042-0. [DOI] [PubMed] [Google Scholar]
  4. Couchman J. R., Yates J., King R. J., Badley R. A. Changes in microfilament and focal adhesion distribution with loss of androgen responsiveness in cultured mammary tumor cells. Cancer Res. 1981 Jan;41(1):263–269. [PubMed] [Google Scholar]
  5. Darbre P., Yates J., Curtis S., King R. J. Effect of estradiol on human breast cancer cells in culture. Cancer Res. 1983 Jan;43(1):349–354. [PubMed] [Google Scholar]
  6. Desmond W. J., Jr, Wolbers S. J., Sato G. Cloned mouse mammary cell lines requiring androgens for growth in culture. Cell. 1976 May;8(1):79–86. doi: 10.1016/0092-8674(76)90188-4. [DOI] [PubMed] [Google Scholar]
  7. Dexter D. L., Calabresi P. Intraneoplastic diversity. Biochim Biophys Acta. 1982 Dec 21;695(2):97–112. doi: 10.1016/0304-419x(82)90019-1. [DOI] [PubMed] [Google Scholar]
  8. Dexter D. L., Kowalski H. M., Blazar B. A., Fligiel Z., Vogel R., Heppner G. H. Heterogeneity of tumor cells from a single mouse mammary tumor. Cancer Res. 1978 Oct;38(10):3174–3181. [PubMed] [Google Scholar]
  9. Diala E. S., Cheah M. S., Rowitch D., Hoffman R. M. Extent of DNA methylation in human tumor cells. J Natl Cancer Inst. 1983 Oct;71(4):755–764. [PubMed] [Google Scholar]
  10. Doerfler W. DNA methylation and gene activity. Annu Rev Biochem. 1983;52:93–124. doi: 10.1146/annurev.bi.52.070183.000521. [DOI] [PubMed] [Google Scholar]
  11. Drohan W. N., Benade L. E., Graham D. E., Smith G. H. Mouse mammary tumor virus proviral sequences congenital to C3H/Sm mice are differentially hypomethylated in chemically induced, virus-induced, and spontaneous mammary tumors. J Virol. 1982 Sep;43(3):876–884. doi: 10.1128/jvi.43.3.876-884.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fanning T. G., Vassos A. B., Cardiff R. D. Methylation and amplification of mouse mammary tumor virus DNA in normal, premalignant, and malignant cells of GR/A mice. J Virol. 1982 Mar;41(3):1007–1013. doi: 10.1128/jvi.41.3.1007-1013.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Feinberg A. P., Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983 Jan 6;301(5895):89–92. doi: 10.1038/301089a0. [DOI] [PubMed] [Google Scholar]
  14. Felsenfeld G., McGhee J. Methylation and gene control. Nature. 1982 Apr 15;296(5858):602–603. doi: 10.1038/296602a0. [DOI] [PubMed] [Google Scholar]
  15. Fidler I. J., Hart I. R. The origin of metastatic heterogeneity in tumors. Eur J Cancer. 1981 May;17(5):487–494. doi: 10.1016/0014-2964(81)90049-9. [DOI] [PubMed] [Google Scholar]
  16. Gama-Sosa M. A., Slagel V. A., Trewyn R. W., Oxenhandler R., Kuo K. C., Gehrke C. W., Ehrlich M. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 1983 Oct 11;11(19):6883–6894. doi: 10.1093/nar/11.19.6883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gasson J. C., Ryden T., Bourgeois S. Role of de novo DNA methylation in the glucocorticoid resistance of a T-lymphoid cell line. Nature. 1983 Apr 14;302(5909):621–623. doi: 10.1038/302621a0. [DOI] [PubMed] [Google Scholar]
  18. Hager J. C., Fligiel S., Stanley W., Richardson A. M., Heppner G. H. Characterization of a variant-producing tumor cell line from a heterogeneous strain BALB/cfC3H mouse mammary tumor. Cancer Res. 1981 Apr;41(4):1293–1300. [PubMed] [Google Scholar]
  19. Heppner G. H., Dexter D. L., DeNucci T., Miller F. R., Calabresi P. Heterogeneity in drug sensitivity among tumor cell subpopulations of a single mammary tumor. Cancer Res. 1978 Nov;38(11 Pt 1):3758–3763. [PubMed] [Google Scholar]
  20. Kerbel R. S. Implications of immunological heterogeneity of tumours. Nature. 1979 Aug 2;280(5721):358–360. doi: 10.1038/280358a0. [DOI] [PubMed] [Google Scholar]
  21. Kim U., Depowski M. J. Progression from hormone dependence to autonomy in mammary tumors as an in vivo manifestation of sequential clonal selection. Cancer Res. 1975 Aug;35(8):2068–2077. [PubMed] [Google Scholar]
  22. King R. J., Cambray G. J., Robinson J. H. The role of receptors in the steroidal regulation of tumour cell proliferation. J Steroid Biochem. 1976 Nov-Dec;7(11-12):869–873. doi: 10.1016/0022-4731(76)90004-2. [DOI] [PubMed] [Google Scholar]
  23. Michalides R., Wagenaar E., Sluyser M. Mammary tumor virus DNA as a marker for genotypic variance within hormone-responsive GR mouse mammary tumors. Cancer Res. 1982 Mar;42(3):1154–1158. [PubMed] [Google Scholar]
  24. Pellicer A., Wigler M., Axel R., Silverstein S. The transfer and stable integration of the HSV thymidine kinase gene into mouse cells. Cell. 1978 May;14(1):133–141. doi: 10.1016/0092-8674(78)90308-2. [DOI] [PubMed] [Google Scholar]
  25. Razin A., Riggs A. D. DNA methylation and gene function. Science. 1980 Nov 7;210(4470):604–610. doi: 10.1126/science.6254144. [DOI] [PubMed] [Google Scholar]
  26. Sluyser M., De Goeij C. C., Evers S. G. Changes in sensitivity to cyclophosphamide of mouse mammary tumors during serial transplantation. J Natl Cancer Inst. 1981 Feb;66(2):327–330. [PubMed] [Google Scholar]
  27. Smith J. A., King R. J. Effects of steroids on growth of an androgen-dependent mouse mammary carcinoma in cell culture. Exp Cell Res. 1972 Aug;73(2):351–359. doi: 10.1016/0014-4827(72)90058-4. [DOI] [PubMed] [Google Scholar]
  28. Soule H. D., Maloney T., McGrath C. M. Phenotypic variance among cells isolated from spontaneous mouse mammary tumors in primary suspension culture. Cancer Res. 1981 Mar;41(3):1154–1164. [PubMed] [Google Scholar]
  29. Stanley E. R., Palmer R. E., Sohn U. Development of methods for the quantitative in vitro analysis of androgen-dependent and autonomous Shionogi carcinoma 115 cells. Cell. 1977 Jan;10(1):35–44. doi: 10.1016/0092-8674(77)90137-4. [DOI] [PubMed] [Google Scholar]
  30. Waalwijk C., Flavell R. A. DNA methylation at a CCGG sequence in the large intron of the rabbit beta-globin gene: tissue-specific variations. Nucleic Acids Res. 1978 Dec;5(12):4631–4634. doi: 10.1093/nar/5.12.4631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wigler M., Sweet R., Sim G. K., Wold B., Pellicer A., Lacy E., Maniatis T., Silverstein S., Axel R. Transformation of mammalian cells with genes from procaryotes and eucaryotes. Cell. 1979 Apr;16(4):777–785. doi: 10.1016/0092-8674(79)90093-x. [DOI] [PubMed] [Google Scholar]
  32. Yates J., King R. J. Correlation of growth properties and morphology with hormone responsiveness of mammary tumor cells in culture. Cancer Res. 1981 Jan;41(1):258–262. [PubMed] [Google Scholar]
  33. Yates J., King R. J. Multiple sensitivities of mammary tumor cells in culture. Cancer Res. 1978 Nov;38(11 Pt 2):4135–4137. [PubMed] [Google Scholar]

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