Question

(c) Define the terms agonist and antagonist and discuss how the breast cancer drug, tamoxifen, acts an antagonist for the human estrogen receptor while estradiol acts a natural agonist for this same receptor. estradiol tamoxifen

Answer 1

An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. Whereas an agonist causes an action, an antagonist blocks the action of the agonist, and an inverse agonist causes an action opposite to that of the agonist.

Tamoxifen is an "anti-estrogen" and works by competing with estrogen to bind to estrogen receptors in breast cancer cells. Tamoxifen is formally known as a selective estrogen receptor modulator (SERM). By blocking estrogen in the breast, tamoxifen helps slow the growth and reproduction of breast cancer cells.

Estrogens have a major role in the growth and development of target tissues including the mammary gland, where they play a critical role in the regulation of proliferation and differentiation. The biological activities of estrogens are mediated by nuclear estrogen receptors (ERs), which interact directly with estrogen response elements (ERE) in the promoters of target genes and recruit various co-activators to mediate transcriptional regulation (McDonnell and Norris, 2002). ERs also regulate transcription through “non-classical” response sites, probably via protein-protein interactions (McDonnell and Norris, 2002), while they induce non-genomic effects via signalling pathways more commonly associated with growth factor activation of cell surface receptors. The presence of high levels of ERα in benign breast epithelium signifies an increased risk of breast cancer, suggesting a role for ERα in breast cancer initiation, promotion and progression (Ali and Coombes, 2000). While ERα expression has been thoroughly studied, the role of the beta isoform, ERβ, remains controversial. ERα and ERβ share high sequence homology, especially in the regions or domains responsible for specific binding to DNA and to the ligands. Upon activation, ERβ can form homodimers, as well as heterodimers with ERα (Kuiper et al., 1997; Paech et al., 1997). The existence of two ER subtypes and their ability to form DNA-binding heterodimers suggest three potential pathways of estrogen signalling: via the ERα or ERβ subtypes in tissues exclusively expressing each subtype, and via the formation of heterodimers in tissues expressing both ERα and ERβ.

The ERα is an important target to develop drugs for the treatment and prevention of breast cancer (Jensen and Jordan, 2003). The interaction of estrogen with the ER can result in increased proliferation of target cells; accordingly, the rationale for therapy is either to block the interaction of estrogen with the ER or to suppress ERα expression. The role of ERβ in breast cancer growth and development is not as clear as that of ERα (Gustafsson and Warner, 2000; Palmieri et al., 2002).

Currently, there is not enough evidence indicating the effect of estrogen in proteoglycan (PG) and matrix metalloproteinase (MMP) expression. It was found that in breast carcinomas, estrogen may promote pathological tumour-stromal interactions through up-regulation of heparanase gene expression (Elkin et al., 2003), while metastatic breast cancer cells secrete a 52K protein under estrogen stimulation, which seems to be associated with a tumour metastatic capacity. This 52K protein can be activated by estrogen and degrade the basement membrane and some PGs (Capony et al., 1987; Rochefort et al., 1987). It has also been shown that estradiol (E2) regulates MMP-2 and MMP-9 as well as TIMP-1 and TIMP-2 in ER-positive (ER+) human breast cancer cells (Nilsson et al., 2007).

It is well recognized now that, apart from enhanced proliferation, abnormal interactions between tumour cells and surrounding extracellular stromal elements are critical for cancer progression, angiogenesis, and metastasis (Liotta and Kohn, 2001; Shekhar et al., 2001). The molecular basis of such interactions involves enzymatic degradation and remodelling of the extracellular matrix (ECM) (Liotta and Kohn, 2001). Extracellular proteases have been shown to be essential to cell transformation, migration, and differentiation. Several lines of evidence indicate that estrogen and related compounds could participate in the regulation of this process (Wingrove et al., 1998; Ruohola et al., 1999; Losordo and Isner, 2001; Haslam and Woodward, 2001).

Syndecans are a family of transmembrane heparan sulfate proteoglycans widely expressed in both developing and adult tissues. In some cancers, syndecan expression has been shown to regulate tumour cell function (e.g. proliferation, adhesion, and motility) and to serve as a prognostic marker for tumour progression. While all four syndecans have been implicated in the regulation of the cytoskeleton, their roles are still complex. Syndecan-2 has been implicated in cell adhesion and signalling (Tkachenko et al., 2005) and also in the progression of cancer (Beauvais and Rapraeger, 2004; Han et al., 2004). Increased levels of syndecan-2 in lung and colon cancer cells lead to a less adhesive phenotype and a loss of contact inhibition (Dobra et al., 2000; Park et al., 2002), further implicating syndecan-2 in the modulation of the tumorigenic and invasive behaviour of cancer cells. Syndecan-4 may function as an anti-migratory/anti-invasive receptor in cancer cells. Syndecan-4 is down-regulated in colon carcinoma cells (Jayson et al., 1999; Park et al., 2002). Based on its diverse roles linking cell signalling and cell–ECM interactions to the cytoskeleton, syndecan-2 and -4 have a strong potential for development as a therapeutic target for treatment of cancer and other vascular-dependent disease processes.

MMP-9 and TIMP-1 may also provide a strong potential for development as a therapeutic target for treatment of cancer. MMP-9 is related to tumour invasion and metastasis by its capacity for tissue remodelling via extracellular matrix as well as basement membrane degradation and induction of angiogenesis (Sternlicht and Werb, 2001; Egeblad and Werb, 2002; Mitropoulou et al., 2003; Stahtea et al., 2007). TIMP-1 is expressed by a range of different cell types and is present in a variety of body fluids and tissues (Welgus and Stricklin, 1983). Besides the MMP inhibitory function, several other functions have been suggested for TIMP-1. These include antiapoptotic, growth promoting and possibly both proangiogenic and antiangiogenic effects (Fernandez et al., 1999; Li et al., 1999; Luparello et al., 1999; Lafleur et al., 2002). In the present study, we investigated how E2 affects the above ECM macromolecules using ERα suppression as a possible mechanism of such regulation.

Based on the above it seems that syndecan-2 and -4, as well as MMP-9 and TIMP-1 represent potential therapeutic targets for breast cancer treatment.