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Hormonal Status in Breast Cancer
In the UK, breast cancer is the most common cancer type, affecting around 1 in 8 women. It can be loosely divided into non-invasive, where the cancer is localised to the ducts or lobules in which it originated, or invasive, where the cancer cells have spread beyond the initial duct or lobule into the surrounding breast cancer or other part of the body. Risk factors that may predispose to breast cancer include increasing age and a family history of breast cancer. Despite the increase in incidence of breast cancer with age, there is a notable deceleration of this increase following menopause. Moreover, breast cancer risk is heightened following use of the combined oral contraceptive pill and combined HRT. Armed with this evidence that endogenous and exogenous changes in oestrogen and progesterone levels modulate the risk of breast cancer, it is apparent that hormones can play a key role in breast cancer.

Indeed, breast tumours can express certain steroid hormone receptors, and use these to grow and proliferate. These steroid hormone receptors are the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Immunohistochemical analysis of a tumour sample, taken via biopsy or after surgery, is utilised to determine the presence of these receptors. To classify a tumour as ER or PR negative or positive, the Allred score is utilised, which takes into account both the proportion of ERs and PRs present and the overall intensity score of the staining - this method is considered controversial, however. The overexpression of HER2 is determined by immunohistochemistry, or with fluorescent in situ hybridisation in those equivocal cases where IHC does not provide a clear result.

Different molecular subtypes have also been described, which loosely align with receptor status:


 * Luminal A (ER and/or PR positive; HER2 negative)
 * Luminal B (ER and/or PR positive; HER2 positive)
 * HER2-enriched (ER/PR negative; HER2 positive)
 * Basal like (triple negative).

Additionally, cancers can be ER-/PR+ or ER+/PR-, but these are unnamed and relatively rare. The receptor status of a cancer is assessed for all breast cancers as it has important implications on prognosis of the patient. It also dictates the treatment given: cancers that do express ER are likely to respond to endocrine therapy, but this type of therapy will have no effect on triple-negative breast cancers.

Mechanism of Estrogen Receptor Action
75% of breast cancers are ER+. ER is a transcription factor containing a DNA-binding domain which allows binding DNA at specific sequences called estrogen response elements (EREs), defined as 5’-GGTCAnnnTGACC-3’, where n refers to any nucleotide. The N-terminal of the ER holds the activation function 1 (AF1) domain; the AF2 domain of the ER is contained within the ligand binding domain. The AF2 domain contains binding sites for coactivators.

Estrogen is a steroid hormone and can cross the cell membrane freely. It can then bind to an ER, which is located in the cytoplasm of the cell. Upon binding, the ligand-receptor complex dimerises with another, and this homodimer moves into the nucleus. Binding of an estrogen ligand exposes a site on the AF2 domain for co-activators to attach to the ER. By recruiting coactivators and transcription factors, transcription of downstream genes, referred to as estrogen responsive genes, is initiated. These genes are of diverse function, but may potentiate aberrant cell survival and proliferation, contributing to tumorigenesis and cancer progression. For example, the ER can promote transcription of cyclin D1, an important regulator of the cell cycle. By interfering with the expression of this regulator, estrogen and estrogen receptor signalling can disrupt the cell cycle.

Endocrine therapies interrupt this pathway, blocking the binding of the receptor to the response element and subsequent transcription of these estrogen-responsive genes. ER+/PR+ cancers have been found to show better results with administration of SERMs than ER+/PR- cancers. This trend has been found with AI therapy also, albeit in fewer studies. The biological basis of this remains unknown.