Originally published as JCO Early Release 10.1200/JCO.2008.19.5909 on November 10 2008

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Speirs, V. Articles by Shaaban, A. M. Search for Related Content PubMed PubMed Citation Articles by Speirs, V. Articles by Shaaban, A. M. Related Articles Related Reply Related Article Social Bookmarking                            What's this?

Clinical Importance of Estrogen Receptor β Isoforms in Breast Cancer

Valerie Speirs, Andrew R. Green, Thomas A. Hughes, Ian O. Ellis, Philippa T.K. Saunders, Abeer M. Shaaban

Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom; Department of Histopathology, Nottingham University Hospitals Trust and University of Nottingham, Nottingham, United Kingdom, Medical Research Council Human Reproductive Sciences Unit, Queen's Medical Research Institute, Edinburgh, United Kingdom

To the Editor:

Since its discovery in 1996,¹ progress in understanding the potential role of estrogen receptor β (ERβ) in the clinical management of breast cancer has been hindered by the publication of contradictory data from studies that used small numbers of cases, relied on poorly validated primary antibodies, or failed to account for the contribution of the five known ERβ isoforms.^2,3 Recently, the situation has improved through the publication of two large studies. In Journal of Clinical Oncology, in one of the largest immunohistochemical studies conducted to date, Honma et al⁴ examined total ERβ, ERβ1, and ERβ2 in 442 breast tumors from a group of Japanese patients who all received tamoxifen monotherapy. They showed that ERβ1 was an independent predictor of recurrence, disease-free survival, and overall survival, particularly in the so-called triple-negative breast cancers, which do not express ER, progesterone, or HER2. In our immunohistochemical study, we evaluated expression of ERβ1, ERβ2, and ERβ5 in a cohort of 880 unselected breast tumors of European origin.⁵ In contrast to the Honma et al study, our study revealed that ERβ2 was the most significant ERβ isoform in breast cancer, as it was predictive of disease-free and overall survival and response to hormone therapy. Using the same antibody as Honma et al,⁴ we found that ERβ1 was uninformative, irrespective of scoring method or cutoff used. Our study revealed a moderate association of ERβ5 with improved survival, but only when it was strongly expressed. It is possible that ethnic differences between the two cohorts may have contributed to these contrasting observations, as significant differences in expression of ERβ isoforms have been reported at the mRNA level in African-American versus Caucasian women.⁶ A comparison of these cohorts showed that the former group expressed significantly higher levels of ERβ1 and, in particular, ERβ5. No differences were seen with ER, and ERβ2 was not examined. These three studies^4-6 strongly suggest that the specific type and level of ERβ isoform expression may contribute to breast cancer survival across different ethnic groups.

Finally, the presence of cytoplasmic ERβ immunoreactivity has been consistently noted in a number of studies, including that of Honma et al.⁴ We have formally examined this and have shown that the cellular location of ERβ isoforms determines outcome. Although nuclear ERβ2 predicted good clinical response, cytoplasmic ERβ2 expression, alone or combined with nuclear staining, predicted significantly worse overall survival. Notably, patients with only cytoplasmic ERβ2 expression had significantly worse outcomes.⁵

In summary, not only does the type of ERβ expressed influence survival, but the cellular location of ERβ isoforms, in particular ERβ2, has distinct prognostic outcome in breast cancer. We suggest that ERβ isoforms should be considered in translational arms of future breast cancer trials to determine whether they can provide additional clinically useful information to oncologists involved in direct breast cancer treatment.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

NOTES

published online ahead of print at www.jco.org on November 10, 2008.

REFERENCES

1. Kuiper GG, Enmark E, Pelto-Huikko M, et al: Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A 93:5925-5930, 1996[Abstract/Free Full Text]

2. Speirs V, Carder PJ, Lane S, et al: Oestrogen receptor β: What it means for patients with breast cancer. Lancet Oncol 5:174-181, 2004[CrossRef][Medline]

3. Moore JT, McKee DD, Slentz-Kesler K, et al: Cloning and characterisation of human estrogen receptor β isoforms. Biochem Biophys Res Comm 247:75-78, 1988[CrossRef]

4. Honma N, Horri R, Iwase T, et al: Clinical importance of estrogen receptor-β evaluation in breast cancer patients treated with adjuvant tamoxifen therapy. J Clin Oncol 26:3727-3734, 2008[Abstract/Free Full Text]

5. Shaaban AM, Green AR, Karthik S, et al: Nuclear and cytoplasmic expression of ERβ1, -2 and -5 identifies distinct prognostic outcome for breast cancer patients. Clin Cancer Res 14:5228-5235, 2008[Abstract/Free Full Text]

6. Poola I, Fuqua SAW, De Witty RL, et al: Estrogen receptor -negative breast cancer tissues express significant levels of estrogen-independent transcription factors, ERβ1 and ERβ5: Potential molecular targets for chemoprevention. Clin Cancer Res 11:7579-7585, 2005[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Reply

• In Reply
  Naoko Honma, Shigehira Saji, and Mamoun Younes
  JCO 2008 26: 5825-5826 [Full Text]

Related Article

• Clinical Importance of Estrogen Receptor-β Evaluation in Breast Cancer Patients Treated With Adjuvant Tamoxifen Therapy
  Naoko Honma, Rie Horii, Takuji Iwase, Shigehira Saji, Mamoun Younes, Kaiyo Takubo, Masaaki Matsuura, Yoshinori Ito, Futoshi Akiyama, and Goi Sakamoto
  JCO 2008 26: 3727-3734 [Abstract] [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Speirs, V. Articles by Shaaban, A. M. Search for Related Content PubMed PubMed Citation Articles by Speirs, V. Articles by Shaaban, A. M. Related Articles Related Reply Related Article Social Bookmarking                            What's this?