Estrogen is commonly referred to as a sex hormone due to its key role in the development of secondary sex characteristics and the regulation of the female reproductive system. However, its effects are much more wide-reaching, impacting the immune and cardiovascular systems, bone density and metabolic processes.
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The biological effects of estrogen are mediated through its binding to structurally and functionally distinct estrogen receptors. The estrogen receptor is consequently of pharmaceutical interest as a target for the treatment of osteoporosis, breast cancer, and other female endocrine disorders.
The estrogen receptor
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.
Role of estrogen in breast cancer
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.
ERα as a therapeutic target
The pivotal role of ERα in the etiology of breast cancer also makes it a key target for breast cancer treatments. Interfering with estrogen signaling can prevent or reduce the proliferation of cancerous cells. Consequently, a range of endocrine therapies is now available that disrupt the activation of ERα by estrogen. This goal has been achieved with a variety of agents with distinct mechanisms of action.
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, thereby reducing the opportunity for estrogen stimulation.
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, with their various of modes of action, the cornerstone of treatment strategies for the management of ER+ breast cancers.
Interaction between estrogen and ERα is fundamental to the survival and progression of ER+ breast cancers. Overactivity of ERα is observed in more than three quarters of all breast cancers. Minimizing ERα activity or reducing the number of estrogen receptors within breast cancer cells can provide effect treatments for breast cancers that express the estrogen receptor.
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