Selective Estrogen Regulation Analysis

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According to the Breast Cancer Network of Australia, breast cancer is the second leading cause of female mortality and accounts for approximately 28% of newly diagnosed cancer cases within Australian women (Bcna.org.au, 2018). A large proportion of breast cancer formation is said to be estrogen-dependent or estrogen-positive (ER+), meaning the growth of the tumor is dependent on availability of estrogen (Brenner and Stevens, 2013). This had led to the formulation of pharmaceutical products which targets the estrogen receptors present within cells, such as Selective Estrogen Receptor Down-regulators (SERD) and Selective Estrogen Receptor Modulators (SERM) (Howell, Johnston and Howell, 2004). These endocrine therapies are used to control estrogen …show more content…
The expression of these two ER differ not only between tissue but also cell types with ERα mainly found within uterus, breast, liver and white adipose tissue while ERß predominates within bone marrow, colon and vascular endothelium (Dahlman-Wright et al., 2006). The steroid hormone estrogen (17ß-estradiol) binds to these receptors within target organs and elicits a range of biological responses, such as the development of reproductive organs and characteristics, as well as cardio protective and metabolic processes (Lee, Kim and Choi, 2012). The binding of estrogen to the receptor results in a conformational change and formation of receptor dimers that allow for interaction with DNA, and regulatory modulation of target genes (Kuiper et al., 1998). As such, estrogen receptors have become the target element for drugs which seek to alter the activity of estrogen in regard to breast cancer and menopausal …show more content…
Tamoxifen is one such drug and is classed as a Selective Estrogen Receptor Modulator (SERM), due to its ability to act as both an antagonist and agonist at estrogen receptors (Howell, Johnston and Howell, 2004). It competitively binds to the estrogen receptor causing a conformational change within the coactivator-binding pocket, inhibiting eventual target gene promotion (Wittmann, Sherk and McDonnell, 2007). These mechanisms have noteworthy implications on treatment for ERα-positive breast cancers, as growth of these tumors is dependent upon 17ß-estradiol interaction (Wittmann, Wardell and Norris, 2015). However, repeated administration of SERMs can lead to development of acquired resistance (McDonnell, Wardell and Norris, 2015). Selective Estrogen Receptor Down-regulators (SERD) exhibit comparable affinity to ER but do not display the agonistic effects of SERMs (Howell, Johnston and Howell, 2004). They share the same characteristic effects as SERMs, in terms of changes in receptor conformation, but there is a more pronounced and significant down-regulation and turnover rate of ERα (Wittmann, Sherk and McDonnell, 2007). The only clinically used SERD, Faslodex (Fulvestrant), is somewhat limited in its use as it must be administered intramuscularly due to poor oral bioavailability
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