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Multiple mechanisms of estrogen receptor gene repression contribute to ER-negative breast cancer

The Pharmacogenomics Journal volume 3, pages 251–253 (2003)Cite this article

For 30 years, we have determined the presence of ER in breast cancer and used the information for treating patients. Yet, in spite of methodological advances, we still lack a complete understanding of basic aspects of ER expression. Since the breast is a target organ for estrogens and the physiological response to estrogens is dependent on the presence of ER, one would expect normal mammary epithelial cells to express ER. However, immunohistochemical studies showed that less than 20% of normal epithelial cells are ER positive.1 In contrast, some breast cancers contain 60% or more ER-positive tumor cells. Thus, we have the paradoxical situation that the expression of the physiological mediator ER is increased in mammary malignancy compared to normal breast. Having just said that epithelial cells are more frequently ER positive in breast cancer than in normal breast, we have to admit a second unexplained fact, that is, 20–30% of breast cancers are ER negative at the time of diagnosis. Two opposing models have been advanced to account for ER-positive and -negative tumors.2 The two-stage model proposes that ER-positive and -negative tumors represent different stages in the breast cancer disease process, that is, breast cancers are initially ER positive and lose their hormone dependence through clonal evolution, resulting in ER-negativity. The second model proposes that the receptor status is a fundamental characteristic of each tumor, not a marker of the degree of differentiation of the tumor cells. Thus, ER status defines different types of breast cancer, which arise by different disease processes and may reflect different etiologies. To explain the ER-negative status and to validate the correctness of either model requires a better understanding of deficient ER expression.

The majority of studies have examined ERα, the predominant receptor isoform in breast tissue, which accounts for most of the hormone binding in ER-positive tumors. Alterations of the ERα gene in the form of point mutations, deletions, or insertions are rare events that do not explain the ER-negative status of 20–30% of breast cancers.3 Stable changes in gene expression can result not only from genetic but also epigenetic mechanisms, that is, changes to chromatin that do not affect the DNA sequence. The basic repeating unit of chromatin is the nucleosome, typically composed of an octamer of the four core histones H2A, H2B, H3, and H4 and 146 base pairs of DNA wrapped around the histones. Both DNA and histones can be modified enzymatically, causing structural changes in chromatin and varying degrees of DNA access allowing either transcription or repression of genes. For the past decade, investigators have searched for epigenetic mechanisms to explain ER-negative breast cancer.

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References

  1. Clarke RB, Howell A, Potten CS, Anderson E Cancer Res 1997; 57: 4987–4991.

  2. Parl FF Estrogens, Estrogen Receptor and Breast Cancer Amsterdam: IOS Press 2000.

    Google Scholar 

  3. Roodi N, Bailey LR, Kao W-Y, Verrier CS, Yee CJ, Dupont WD et al. J Natl Cancer Inst 1995; 87: 446–451.

  4. Lapidus RG, Nass SJ, Butash KA, Parl FF, Wietzman SA, Graff JG et al. Cancer Res 1998; 58: 2515–2519.

  5. Rountree MR, Bachman KE, Baylin SB Nat Genet 2000; 25: 269–277.

    Article  CAS  Google Scholar 

  6. Yang X, Phillips DL, Ferguson AT, Nelson WG, Herman JG, Davidson NE Cancer Res 2001; 61: 7025–7029.

  7. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman R et al. Nature 1998; 393: 386–389.

    Article  CAS  Google Scholar 

  8. Macaluso M, Cinti C, Russo G, Russo A, Giordano A Oncogene 2003; 22: 3511–3517.

    Article  CAS  Google Scholar 

  9. Vandel L, Nicolas E, Vaute O, Ferreira R, Ait-Si-Ali S, Trouche D Mol Cell Biol 2001; 21: 6484–6494.

  10. Magnaghi-Jaulin L, Groisman R, Naguibneva I, Robin P, Lorain S, LeVillain JP et al. Nature 1998; 391: 601–605.

    Article  CAS  Google Scholar 

  11. Nielsen SJ, Schneider R, Bauer UM, Bannister AJ, Morrison A, OCarroll D et al. Nature 2001; 412: 561–565.

    Article  CAS  Google Scholar 

  12. Kos M, Reid G, Denger S, Gannon F Mol Endocrinol 2001; 15: 2057–2063.

  13. Wolffe AP, Matzke MA Science 1999; 286: 481–486.

    Article  CAS  Google Scholar 

Download references

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  1. Department of Pathology, Vanderbilt University, Nashville, Tennessee

    F F Parl

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Parl, F. Multiple mechanisms of estrogen receptor gene repression contribute to ER-negative breast cancer. Pharmacogenomics J 3, 251–253 (2003). https://doi.org/10.1038/sj.tpj.6500201

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