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Menopause Live - IMS Updates
InFocus

Date of release: 26 January, 2015

ERβ and breast cancer - knowledge translates into therapy


Estrogen receptor beta (ERβ) was described already some 15 years ago, but received much less attention than ERα. Like ERα, ERβ is a member of the nuclear receptor superfamily of proteins that functions as a ligand-mediated transcription factor. The DNA binding domains of ERα and ERβ share 96% homology at the amino acid level; however, the remainder of the protein domains is highly divergent. About three-quarters of breast tumors express ERα, which is therefore the major marker that determines therapy with either selective estrogen receptor modulators (SERMs) or aromatase inhibitors. While ERβ is highly expressed in normal breast tissue, a number of immunohistochemistry-based studies have demonstrated conflicting data with regard to ERβ expression in breast tumors [1]. Also, the association between ERβ and disease recurrence, disease-free survival, overall survival and prognosis is conflicting. Reese and colleagues [1] examined three patient cohorts: 184 women who underwent primary breast cancer surgery (retrospective analysis); 68 patients who underwent primary breast cancer surgery selected for having a triple-negative breast cancer (TNBC) (retrospective analysis); and 258 eligible patients enrolled into a prospective adjuvant tamoxifen study in postmenopausal women with early-stage ERα-positive breast cancer. Their results revealed that expression of ERβ1 (one of several isoforms of ERβ), while detected in nearly all normal breast epithelium, is lost in many breast cancer tissues. However, the expression of ERβ1 is associated with substantially improved anti-tumor effects in ERα-positive tamoxifen-treated breast cancer, as well as potent anti-proliferative effects in vitro, confirming its role as a tumor suppressor. To note, ERβ1 was expressed in both ERα-positive and ERα-negative (TNBC) breast tumors.

Comment

It is well established that the response of breast cancer to tamoxifen is determined by whether cellular proliferation is ERα-mediated [2]. As opposed to early ductal cancer, which is an ERα-rich, proliferating disease, in early lobular cancer both ERα and ERβ are abundantly expressed and proliferation is rare. In advanced lobular cancer, ERβ is lost, ERα is retained, and proliferation is high. Thus, tamoxifen may be an effective pharmaceutical in late but not early lobular cancer. Recent studies shed more light on the role of ERβ in the physiology of breast cancer cells and on the potential use of its agonists as a novel therapeutic approach for breast cancer. It seems that the main focus is directed at understanding the contribution of ERβ in the case of TNBC. ERβ is often expressed in TNBC, the more aggressive type of breast cancer having limited treatment options because of the lack of expression of a recognized biological target. Results so far are encouraging in the sense of possible addition of ERβ-based medications in the future to the therapeutic strategy against TNBC. For example, Hinsche and colleagues used an in vitro model of TNBC cell invasion [3]. They demonstrated that treatment with ERβ selective estrogen agonists liquiritigenin and ERB 041 reduced the ability to invade a reconstituted basement membrane and to migrate in response to the cellular stimulus. The investigators concluded that ERβ plays a major role in TNBC invasion and that bone -directed invasion can be inhibited by ERβ agonists. In another study, different types of ERβ agonists (WAY-20070 and L17) were used in SERM-resistant breast cancer tissue [4]. Results pointed at a reduction in Bcl-2 expression, and the conclusions were that these agents may become a novel therapeutic pathway in this clinical set-up. This study also incorporated an inhibitor of autophagy, and that drug combination seemed promising. Yet, as mentioned above, perhaps the exact characteristics of the tumor determine whether ERβ agonists would be useful in the fight against breast cancer. There are conflicting data on ERβ as a marker of prognosis, since some studies showed negative results. Guo and colleagues found that ERβ expression is an independent prognostic factor of breast cancer in patients and its high and over-expression indicates poor prognosis of breast cancer [5]. A side issue, but still important is whether ERβ agonists would be effective for the treatment of vasomotor symptoms in women with breast cancer or at high risk for breast cancer. Available preclinical and clinical data with MF101, an oral botanically derived extract that was designed to selectively regulate ERβ, show promise in this respect [6]. As for the endometrium, ERβ is heavily expressed in both normal and tumor cells, as well as in the endometrial vasculature [7]. However, the expected uterine/endometrial neutral effect of novel ERβ selective SERMs has not been conclusively confirmed in long-term studies. To conclude, ERβ agonists seem to be very promising in the treatment of resistant ERα-positive disease and in TNBC, but much more clinical data are needed before clearing it as a safe and effective therapy in humans.

Comentario

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    References

  1. Reese JM, Suman VJ, Subramaniam M, et al. ERβ1: characterization, prognosis, and evaluation of treatment strategies in ERα-positive and -negative breast cancer. BMC Cancer 2014;14:749
    http://www.ncbi.nlm.nih.gov/pubmed/25288324

  2. Huang B, Omoto Y, Iwase H, et al. Differential expression of estrogen receptor α, β1, and β2 in lobular and ductal breast cancer. Proc Natl Acad Sci USA 2014;111:1933-8
    http://www.ncbi.nlm.nih.gov/pubmed/24449868

  3. Hinsche O, Girgert R, Emons G, Grundker C. Estrogen receptor β selective agonists reduce invasiveness of triple negative breast cancer cells. Int J Oncol 2015;46:878-84
    http://www.ncbi.nlm.nih.gov/pubmed/25420519

  4. Ruddy SC, Lau R, Cabrita MA, et al. Preferential estrogen receptor β ligands reduce Bcl-2 expression in hormone-resistant breast cancer cells to increase autophagy. Mol Cancer Ther 2014;13:1882-93
    http://www.ncbi.nlm.nih.gov/pubmed/24785256

  5. Guo L, Zhu Q, Yilamu D, Jakulin A, Liu S, Liang T. Expression and prognostic value of estrogen receptor beta in breast cancer patients. Int J Clin Exp Med 2014;7:3730-3736
    http://www.ncbi.nlm.nih.gov/pubmed/25419426

  6. Leitman DC, Christians U. MF101: a multi-component botanical selective estrogen receptor beta modulator for the treatment of menopausal vasomotor symptoms. Expert Opin Investig Drugs 2012;21:1031-42
    http://www.ncbi.nlm.nih.gov/pubmed/22616988

  7. Hapangama DK, Kamal AM, Bulmer JN. Estrogen receptor β: the guardian of the endometrium. Hum Reprod Update 2014 Oct 10. Epub ahead of print
    http://www.ncbi.nlm.nih.gov/pubmed/25305176