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Estrogen and Breast Cancer: a Nuclear (Receptor) War

Estrogen and Breast Cancer: a Nuclear (Receptor) War

By Dr. Lisa Dwane, Postdoctoral Researcher, Royal College of Surgeons in Ireland


The first link between estrogen and breast cancer was made in the late 1800s, when physician George Beatson, who correctly suspected a link between the endocrine system and breast cell proliferation, removed the ovaries of a 33-year old woman with advanced breast cancer and controlled the growth of her tumours (Clarke, 1998). The young mother astonishingly lived for four years following this surgery; an unheard miracle in an era that offered toxic chemotherapy and debilitating surgical procedures as the only options for advanced cancer. Over a century later our knowledge and understanding of estrogen signalling in breast cancer has significantly progressed. Today, we know estrogen exerts its oncogenic functions through binding and activating the estrogen receptor alpha (ERα), a nuclear receptor which acts as a transcription factor to regulate gene expression.

Nuclear receptors and cancer

The study of nuclear receptors and their involvement in cancer pathways has been a complex yet fruitful journey. This is particularly true for cancers dependent on the body’s endocrine system, such as breast, ovarian and prostate cancers. Breast cancer, the most commonly diagnosed invasive cancer in women worldwide, is highly dependent on ERα with expression observed in 70-80% of diagnosed cases. ERα is undoubtedly the most valuable biomarker in the oncology field and has paved the way for the study of other biomarkers in cancer (Oosterkamp et al., 2014). Using this small protein as a tool to predict both long-term survival of breast cancer patients and their response to certain therapies has saved the lives of millions of women worldwide. Today, ERα remains at the epicentre of cancer research with many labs around the world keen to understand the mechanisms which regulate this nuclear receptor.

ERα signalling and its role in breast cancer

Nuclear receptor signalling is unique in that the ligand can cross the plasma membrane and interact with the receptor within the cell, in contrast to other signalling pathways which depend on ligand recognition at the cell’s surface. The steroid hormone estrogen can function in this way; once it enters the cell it binds to cytoplasmic ERα, and like most other type 1 nuclear receptors acts as a transcription factor to regulate gene expression. First, estrogen-bound ERα dissociates from heat shock protein 90 (HSP90), a molecular chaperone which binds inactive ERα in the cytoplasm. When released, ERα homodimerises and exposes it nuclear localisation sequence for translocation in to the nucleus. Here, ERα interacts with a number of cofactors which facilitate high-affinity binding to estrogen response element (ERE) palindromic sequences on DNA, regulating the expression of ERα target genes (Figure 1) (Sever and Glass, 2013, Bjornstrom and Sjoberg, 2005).

Physiologically, ERα plays an important role in bone development, cardiovascular protection and of importance here, the development of both male and female reproductive systems. ERα regulates and promotes the growth and development of the mammary glands, however, deregulation of this process can result in uncontrolled cell proliferation and the formation of a malignant tumour (Le Romancer et al., 2011). Today, Beatson’s method of removing both ovaries is still used to treat breast cancer, however, our understanding of ERα oncogenic mechanisms have led to the development of ERα targeted-therapies and have provided a less invasive, more reliable treatment (and often cure!) for breast cancer.

Anti-endocrine therapy

Targeted, anti-endocrine therapies either antagonise the receptor (tamoxifen), promote receptor degradation (fulvestrant) or block estrogen synthesis (aromatase inhibitors) (Maximov et al., 2013). Tamoxifen is a selective estrogen receptor modulator (SERM) that competes with estrogen for ERα in breast tissue and ultimately prevents the transcription of estrogen-responsive genes. The year 2017 marked the 40 year anniversary since the Food and Drug Administration (FDA) approved the use of tamoxifen in ERα+ breast cancer and it since has been one of the most prominent therapies in breast oncology. Tamoxifen binding alters the structural conformation of ERα, attenuating coactivator binding and repressing ERα transcriptional activity (Clemons et al., 2002, Heldring et al., 2004). In breast cancer, adjuvant tamoxifen treatment significantly reduces the rate of recurrence and reduces patient mortality, not only during the treatment period but for a decade following (Davies et al., 2013).

Fulvestrant is a pure anti-estrogen. It reversibly binds to ERα monomers, preventing homodimerisation, hindering translocation in to the nucleus and inducing ERα degradation by the proteasome. Early clinical trials showed that fulvestrant was effective in patients previously treated with tamoxifen and aromatase inhibitors (AIs), leading to its FDA approval in 2002 (Ciruelos et al., 2014). AIs, on the other hand, do not directly act on or modulate ERα. Instead, they interfere with estrogen biosynthesis from androgens through suppression of the aromatase enzyme. AIs are often prescribed to postmenopausal women, where ovarian function is already suppressed. In premenopausal women, AIs have little effect on circulating estrogen due to high levels of aromatase substrate in the ovary (Fabian, 2007).

Due to their interaction with small molecules, nuclear receptors represent a very druggable class of proteins and are currently at the forefront of breast cancer research. Moving forward, it may be feasible to indirectly target ERα in breast cancer, opening up options to patients who don’t respond to the above mentioned therapies.

Figure1: Overview of ERα signalling in breast cancer. Ligand-bound ERα dissociates from HSP90, dimerises, and translocates to the nucleus. ERα binds to estrogen response elements, recruits coactivators and initiates transcription of target genes.

References

BJORNSTROM, L. & SJOBERG, M. 2005. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol, 19, 833-42.

CIRUELOS, E., PASCUAL, T., ARROYO VOZMEDIANO, M. L., BLANCO, M., MANSO, L., PARRILLA, L., MUNOZ, C., VEGA, E., CALDERON, M. J., SANCHO, B. & CORTES-FUNES, H. 2014. The therapeutic role of fulvestrant in the management of patients with hormone receptor-positive breast cancer. Breast, 23, 201-8.

CLARKE, M. J. 1998. Ovarian ablation in breast cancer, 1896 to 1998: milestones along hierarchy of evidence from case report to Cochrane review. Bmj, 317, 1246-8.

CLEMONS, M., DANSON, S. & HOWELL, A. 2002. Tamoxifen ("Nolvadex"): a review. Cancer Treat Rev, 28, 165-80.

DAVIES, C., PAN, H., GODWIN, J., GRAY, R., ARRIAGADA, R., RAINA, V., ABRAHAM, M., MEDEIROS ALENCAR, V. H., BADRAN, A., BONFILL, X., BRADBURY, J., CLARKE, M., COLLINS, R., DAVIS, S. R., DELMESTRI, A., FORBES, J. F., HADDAD, P., HOU, M. F., INBAR, M., KHALED, H., KIELANOWSKA, J., KWAN, W. H., MATHEW, B. S., MITTRA, I., MULLER, B., NICOLUCCI, A., PERALTA, O., PERNAS, F., PETRUZELKA, L., PIENKOWSKI, T., RADHIKA, R., RAJAN, B., RUBACH, M. T., TORT, S., URRUTIA, G., VALENTINI, M., WANG, Y. & PETO, R. 2013. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet, 381, 805-16.

FABIAN, C. J. 2007. The what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer. Int J Clin Pract, 61, 2051-63.

HELDRING, N., NILSSON, M., BUEHRER, B., TREUTER, E. & GUSTAFSSON, J. A. 2004. Identification of tamoxifen-induced coregulator interaction surfaces within the ligand-binding domain of estrogen receptors. Mol Cell Biol, 24, 3445-59.

LE ROMANCER, M., POULARD, C., COHEN, P., SENTIS, S., RENOIR, J. M. & CORBO, L. 2011. Cracking the estrogen receptor's posttranslational code in breast tumors. Endocr Rev, 32, 597-622.

MAXIMOV, P. Y., LEE, T. M. & JORDAN, V. C. 2013. The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice. Curr Clin Pharmacol, 8, 135-55.

OOSTERKAMP, H. M., HIJMANS, E. M., BRUMMELKAMP, T. R., CANISIUS, S., WESSELS, L. F., ZWART, W. & BERNARDS, R. 2014. USP9X downregulation renders breast cancer cells resistant to tamoxifen. Cancer Res, 74, 3810-20.

SEVER, R. & GLASS, C. K. 2013. Signaling by nuclear receptors. Cold Spring Harb Perspect Biol, 5, a016709.

24th Aug 2018 ​Dr. Lisa Dwane, Postdoctoral Researcher, Royal College of Surgeons in Ireland

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