Estrogen receptors: how do they work?
The estrogen receptor exists in two forms, ERα and ERβ, that are transcribed from unique genes and have different and specific roles. Both ERα and ERβ are expressed in the glandular epithelium and stroma of the endometrium, but ERα is the major estrogen receptor subtype in mammary epithelium. Binding of estrogen activates the estrogen receptor and causes it to dimerize and translocate to the cell nucleus. Here the receptor dimer binds to specific estrogen response elements in the target gene promoter, stimulating gene transcription. Hormone binding also induces a conformational change within the ligand-binding domain of the receptor. This enables the recruitment of co-activator proteins that exert a range of non-genomic actions, such as the activation of various protein-kinase cascades. Signaling via estrogen receptors is thus complex and tightly regulated under normal conditions.
ER expression in breast cancers
Estrogen has been implicated in certain human mammary cancers for over a century; regression of mammary cancer was achieved by oophorectomy in 1896. It was not until 1952 that Huggins and Bergenstal demonstrated that some mammary cancers were not autonomous but under the partial control of the endocrine system.It is now well established that estrogen and ERα play a key role in the development and progression of the majority of breast cancers. ERα is present and over-active in 75% of all breast cancers and drives neoplasia. Deregulation of ERα has been shown to promote metastasis in breast cancer cells expressing the estrogen receptor (ER+ breast cancer).
ERα expression is thus a hallmark of hormone-dependent tumour growth and has become a key biomarker for predicting prognosis and treatment response in patients with breast cancer. The estrogen receptor status of breast cancer cells is routinely determined in clinical practice to inform treatment decisions. Compared with tumors that do not express ERα, ER+ breast cancers have a better differentiated morphologic appearance, exhibit stronger clinical responses to hormonal treatment, and incidence rates increase with age rather than slowing after the menopause.
Determining estrogen receptor status
A biopsy of the tumor is obtained and the sample evaluated for the presence of estrogen receptors using an immunohistochemical staining assay. On viewing, only the cells presenting estrogen receptors will be highlighted. The proportion of cells that stain positive for estrogen receptors will then be determined. This may be presented as a percentage from 0% (no estrogen receptors present) to 100% (all cells have estrogen receptors) or as an Allred score. The Allred scale runs from 0 to 8. The score is a combination of the percentage of cells that test positive for estrogen receptors and the intensity of the stain. The higher the score, the more receptors are present. The proportion of estrogen-receptor positive cells required to achieve a classification of ER+ varies between laboratories. However, a score of 0 definitively indicates that the cancer is ER‑.
How ER status influences therapeutic choices
Although metastatic breast cancer is incurable, treatment to slow the growth of the tumor can significantly extend life expectancy. Endocrine therapies are often the treatment of choice due to their more favorable side effect profile. However, as the disease progresses, these will need to be augmented with chemotoxic treatments. It is common for women with ER+ breast cancer to be recommended a type of endocrine therapy. Different therapies have different modes of actions, with some targeting estrogen while others act on the estrogen receptor. They may be used alone or in combination to maximize efficacy. The choice of treatment is selected on a patient-by-patient basis according to their particular situation and cancer type. For example, in pre-menopausal women, the ovaries will still be producing estrogen so therapies that prevent peripheral estrogen synthesis, such as aromatase inhibitors, will be of little benefit used alone in these patients. Even cancers with low numbers of estrogen receptors may respond to estrogen-targeted therapies. In such cases, they will be used in combination with chemotoxic agents or another targeted agent specific for a different receptor, such as PR or HER, that has a greater presence.
Endocrine therapy: what is that about?
Endocrine therapy is commonly used to treat estrogen receptor positive recurrent breast cancer and metastatic breast cancer. The wide variety of available endocrine agents act to prevent the stimulation of breast cancer cells by the hormone estrogen. This is achieved through several different modes of action; these can generally be assigned to one of three main categories: aromatase inhibition, selective estrogen-receptor modulation, and selective estrogen-receptor degradation. These various types of endocrine therapy have been successfully used to significantly reduce cancer recurrence rates and extend survival. Since endocrine therapy targets only estrogen and the estrogen receptor, it can be associated with fewer and less severe side effects than cytotoxic treatments. The side effects of endocrine therapies manifest as menopausal symptoms, such as hot flushes, night sweats and mood changes. However, anti-tumor efficacy can only be achieved with an endocrine therapy if the breast cancer is hormone-sensitive. This typically necessitates expression of the estrogen receptor on the surface of the tumor cells (ER+).
Depending on the type of endocrine therapy used, it will either reduce the amount of estrogen available to activate the receptor, reduce the binding of estrogen to the receptor or reduce the number of estrogen receptors. In each case the cancer cells no longer receive the estrogen stimulation that promotes their growth. By virtue of maintaining a better quality of life, endocrine therapy is often the first-line treatment of choice for ER+ metastatic breast cancer. The majority of breast cancers (75‑80%) are hormone responsive, so this is the most common course of action. In pre-menopausal women, endocrine therapy will be used in conjunction with an ovarian-suppression treatment to prevent the ovaries from producing estrogen. After the menopause, women naturally produce only small amounts of estrogen and so the endocrine therapy can be used alone as estrogen suppression is not required. The efficacy of endocrine therapy may be impaired if the tumor also tests positive for human epidermal growth factor receptor (HER2/HER+), in which case a HER2/HER targeted therapy can be used concomitantly.
The main classes of endocrine therapies for ER+ breast cancers are: estrogen receptor degraders, estrogen receptor modulators, aromatase inhibitors and ovarian suppression. The class or combination of classes prescribed often varies depending on whether the patient is pre- or post- menopausal. Some endocrine therapies prevent the stimulation of ERα by reducing estrogen production, either by stopping the signal for estrogen to be produced, eg, gonadotropin-releasing hormone analogues, or by blocking the estrogen synthesis pathway with aromatase inhibitors. Other endocrine therapies target the receptor itself either preventing estrogen from binding to the ERα and degrading the ERα. The high specificity of these treatments reduces unwanted systemic effects and the likelihood of adverse effects. The resultant highly favorable tolerability profile in conjunction with good tumor control has made the broad group of endocrine therapies the cornerstone of treatment strategies for the management of ER+ breast cancers.
Endocrine resistance: the intrinsic type
Tumor cells that do not express the estrogen receptor are described as receptor negative (ER‑) and are not dependent on estrogen. Consequently, their growth is not hindered by endocrine therapy. If a tumor is not responsive to estrogen, strategies to reduce estrogen stimulation will have no impact on the growth of that tumor. Such tumors are said to have intrinsic endocrine resistance. An alternative first-line therapy is thus required for cases of ER‑ metastatic breast cancer. This commonly takes the form of chemotherapy. If the tumor is HER2/HER+, treatment with an HER2/HER targeted therapy may be used alone or in combination with chemotherapy.
Endocrine resistance: the acquired type
A further obstacle to the success of endocrine agents in the treatment of breast cancer is the tendency of ER+ tumor cells to progressively develop resistance to endocrine therapy during the course of treatment (acquired resistance). It is estimated that with ongoing endocrine therapy, around a third of women with early-stage breast cancer will become refractory to the treatment within 2 to 5 years. eThe development of resistance to an endocrine therapy does not necessarily mean the patient has to start chemotherapy, although this is likely to be required in the longer term. Efficacy may be restored by switching to a different endocrine therapy that has an alternative mode of action. Indeed, a patient may benefit from switching treatment several times in order to extend the duration of efficacy with a better-tolerated endocrine agent.
The precise mechanism underlying the development of endocrine resistance has yet to be determined, but it is thought to arise as a result of complicated crosstalk, both genomic and non-genomic, between estrogen receptors and growth factors. Although the precise pathways have yet to be elucidated, treatments have been identified that reverse endocrine resistance, presumably by disrupting such pathways. These treatments include cyclin-dependent kinase (CDK) inhibitors and phosphoinositide 3-kinase (PI3K) inhibitors, which can be used in combination with endocrine therapies to restore sensitivity and promote tumor shrinkage. Usually these new classes of agents are highly effective eve in most of resistant breast tumors. However, in some cases even a chemoresistance to theses drugs has been reported.
Scientists deem that the reason behind this phenomenon lies int he highly complex and heterogeneous environment cancer itself is made of. Even among billions of cancer cells, there must be at least one which already possesses a mutation that, int ime, will make a significant mass itself resistant to a new drug. Most of aggressive cancers have an high proliferation, mitotic index and metastasis propension: CDK inhibitors and PI3K inhibitors have developed actually to counteract this. CDK inhibitors block cyclin-dependent kinases involved in cell duplication, while PI3K inhibitors interfere with the PI3K-cAkt axis that suppresses programmed cell death. Yet, there are increasing cases among clinical practice where resistance against these molecules has sprung and keeps developing.
Most of the times, CDK- or PI3K inhibitors have veen administered in breast cancer patients along with cytotoxic agents, immunotherapy, aromatase inhibitors, anti-estrogens and targeted therapies. In most of the cases ther is a full and exciting response that may last a while. However, the plastic nature of animal cells will find a way to adapt amongst all those “insults” to develop a way to survive them. There are hundreds of papaers published every year on this topic; scientists are trying their best to come up with even more effective solutions or combinations, studying new informations from basic science. There is no match comparing nowadays to the past about achievements and patient survival. And there is much more that can be done against that seven-headed old acquaintance called cancer.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
Cortesi L, Rugo HS et al. Target Oncol. 2021 Mar 12.
Chang DY et al. Ther Clin Risk Manag. 2021; 17:193-207.
Sobhani N, Fassl A et al. Cells. 2021 Feb 1; 10(2):293.
Migliaccio I et al. Cancer Treat Rev. 2021; 93:102136.
Miricescu D, Totan A et al. Int J Mol Sci. 2020; 22(1):173.
Galván Morales MA et al. Molecules. 2020; 25(23):5686.
D’Souza A et al. J Hematology Oncology 2018; 11:80.
Reinert T et al. Ther Adv Med Oncol 2017; 9(11):693–709.
Brufsky AM. Cancer Treatment Rev 2017; 59:22–32.
Rugo HS et al. J Clin Oncololgy 2016; 34:3069–3103.
Fan W et al. Future Med Chem. 2015; 7(12):1511–19.
Nagaraj G et al. Breast Cancer Res Treat 2015; 150:231.
Mitri Z et al. Chemother Res Pract. 2012; 2012:743193.
Gruvberger S et al. Cancer Research 2001; 61:5979-84.