STEROID HORMONES AND CANCER
Having noted that most signalling molecules, that is hormones, are proteins and don’t need to get into cells to deliver their message, we should mention a second group that works in a completely different way. These are the steroid to all because they include the sex hormones testosterone and oestrogen. All steroids are synthesised using cholesterol as a precursor, also familiar because, we are often told, too much of it is a bad thing (Fig. 1).
2. Cholesterol and derivatives.
Cholesterol itself is a rigid ring with a fatty (acid) molecule attached to it. That suggests cholesterol might be a membrane component and indeed in plasma membranes, there’s, roughly, one cholesterol for every phospholipid. Because of its rigid ring, cholesterol has the effect of limiting the flexibility of the phospholipid fatty acid chains – in other words, cholesterol determines the fluidity and the permeability of membranes.
The various modifications that give rise to the steroid hormones convert cholesterol from an essential structural component of cells to molecules that can act as signals. The major steroid hormones are vitamin D, cortisol (or hydrocortisone, the major human glucocorticoid), oestrogens, progesterone and testosterone (which is a member of the androgen family). All these steroids are pretty insoluble in water, which means that to be carried around the circulation they need to attach to something that is soluble; the most common carrier is the protein serum albumin (which accounts for about 60% of the protein in plasma, the fluid in which blood cells are suspended). When these complexes come into contact with cells the steroid hormone can leave its carrier and diffuse into the lipid environment of the plasma membrane. By this means the hormone’s signal is delivered to the cell and, to the protein hormones, the messenger actually enters the cell and completes the journey to the nucleus to direct gene expression. They can do this because mammalian cells make specific proteins to which steroid hormones bind.
These receptors are members of the nuclear receptor superfamily of transcription factors. Steroid hormone receptors may function as monomers or dimers but all contain a conserved DNA binding domain that recognises consensus DNA sequences (hormone responsive elements or HREs) in the of genes. Inactive receptors are usually bound to proteins that repress their activity as transcription factors. The conformational change caused by ligand binding proteins and permits co-activator proteins to bind to activate transcription. For some receptors, however, hormone binding creates a complex that represses transcription. The cell-specific expression of receptors and co-regulatory proteins determines the transcriptional profile of gene expression in response to individual hormones.
There are four major categories of steroid hormone receptors:
Type I (hormone binds to a receptor in the cytosol causing dissociation of heat shock proteins and translocation to the nucleus. The HREs for type I receptors are two half-sites separated by a variable number of bases, the second site being an inverted repeat of the first). Examples: receptors for oestrogen, glucocorticoid, progesterone and testosterone (Fig. 2).
2. Type I steroid hormone receptor mechanism.
Type II (in the absence of hormone remain bound to DNA as heterodimers, usually with retinoid X receptor alpha (RXRα)). Hormone binding promotes an exchange of co-repressor for co-activator proteins). Examples: receptors for vitamin D, retinoic acid and thyroid hormone (Fig. 3).
3. Type II steroid hormone receptor mechanism.
Type III (similar to type I but HRE is a direct rather than an inverted repeat). They are orphan receptors. Type IV (receptors bind as monomers or dimers but HRE comprises a single half-site).
Steroid hormones are particularly important in cancer because oestrogens can stimulate and endometrial tumours and androgens may accelerate prostate tumours. Thus, for example, oestrogen receptors are over-expressed in 70% of breast cancers (referred to as ER-positive). Both ER and progesterone receptor status are used to predict response to endocrine therapy (i.e. treatment that modulates the effect of hormones). Thus ER+/PR+ tumours respond much better than do ER+/PR- tumours. Since 1980 tamoxifen has been the standard anti-oestrogen therapy for breast cancer because it can antagonise the action of oestrogen. Tamoxifen is a selective oestrogen receptor modulator (SERM). It is a pro-drug metabolised by cytochrome P450 to active forms that compete with oestrogen in binding to ERs. It is ‘selective’ because it shows tissue specificity: in the endometrium, it acts as a partial agonist of the ER. In breast cells, however, ER/tamoxifen complexes bind to DNA and recruit co-repressors that inhibit transcription of genes activated by ER/oestrogen. Oestrogens are synthesised from androgens by the enzyme aromatase, recently aromatase inhibitors (anastrozole, letrozole) have been introduced as anti-cancer agents that work by lowering the level of oestrogen.
The critical feature of receptor tyrosine kinases (RTKs) is that when they are activated by their specific hormone ligands, their kinase activity is switched on to phosphorylate tyrosine amino acids in the cytosolic regions of the receptors themselves. This creates a ‘scaffold’ of phosphate-bearing tyrosines to which cellular proteins bind. These may be adaptors or enzymes and they initiate intracellular pathways that ultimately signal changes in the pattern of gene transcription in the nucleus to turn on the cell leads to proliferation. Highly conserved across all animal species is the mitogen-activated protein kinase (MAPK) pathway in which a molecular switch (the RAS protein) turns on a cascade of kinases leading to the phosphorylation (and hence activation) of protein transcription factors. One of the most important genes whose expression is essential for mammalian cell proliferation is MYC that acts as a ‘master regulator’ because it is a transcription factor that controls about 15% of all human genes. Although the most prominent regulators of cell division, other types of a receptor can be involved, notably G-protein-coupled receptors. Steroid hormones are a separate class of chemical messengers that cross the plasma membrane and, through specific intracellular receptors, interact directly with DNA to control gene transcription.