Mechanisms Of Hormone Action: II Intracellular
Receptors
Clinical background
Estrogen stimulates the proliferation of breast cancer tissue and
exposure to estrogens may be important in the pathogenesis of this disease.
During the treatment of women with breast cancer it is routine practice to
establish the presence (ER +ve) or absence (ER -ve) of estrogen receptors in
cancer cells. Women who have ER + ve
tumours are more likely to respond to endocrine manipulation following surgery
and/or chemotherapy (50–60% response rate in ER +ve cancers, 5–10% in ER−ve
tumours). The most commonly used endocrine therapy is the drug tamoxifen which
has estrogen-antagonist effects in the breast, probably mediated by the
recruitment of corepressors for estrogen receptor action. It produces a
significant fall in tumour recurrence and death rates for women with ER +ve
disease, irrespective of age. The possible use of tamoxifen and the newer,
selective estrogen receptor modulator drugs (SERMs, e.g. raloxifene, toremifine) for the prevention of breast cancer
are under investigation. Trastuzumab, a humanized IgG1 against human epidermal
growth factor receptor-2 (HER-2+), is now used to treat early breast cancer
that overexpresses HER-2.
Intracellular receptors
Lipophilic hormones, such as steroids and the thyroid hormones, pass
easily through the plasma membrane into the cell, where they combine with specific
receptor proteins (Fig. 4a). In the inactive state, for the subfamily of
glucocorticoid, progesterone, estrogen and androgen receptors, the receptor is
bound to a heat shock protein (HSP 90; Fig. 4b).
When the hormone binds to the receptor, the HSP dissociates from it, the
receptors form homodimers and the hormone– receptor complex binds to DNA at
specific sites, termed hormone response elements (HREs), which lie upstream
from transcription initiation sites. Transcription and subsequent protein synthesis
are altered. The thyroid hormone and retinoic acid receptors are not associated
with HSPs in their inactive state, and are able to associate with their
response elements on the DNA in the absence of the hormones, and act as
transcription inhibitors (see also below). Activation of receptors expressing
the actions of the hormones appears to be achieved through phosphorylation,
although at present this process is poorly understood.
Nature of the steroid receptor
The steroid receptors form part of a larger ‘superfamily’ of nuclear
DNA-binding receptors, including androgen, estrogen, glucocorticoid, thyroid
and vitamin D receptors (Fig. 4c). They all have two main regions, a
hydrophobic hormone-binding region and a DNA-binding region, which consists of
two ‘zinc fingers’, rich in cysteine and basic amino acids. The structures of
the receptors are known. Region 1 is the DNA-binding region, and is the most
conserved among the members of the receptor family, in that it has a high
sequence homology from receptor to receptor, as shown in Fig. 4c. It is thought
that the first zinc finger determines the specificity of the binding of the
receptor to DNA, while the second finger stabilizes the receptor to its
response element of the DNA. Regions 2 and 3 of the receptors determine the hormone specificity of binding, and are not
well conserved among the different receptors.
Estrogen receptors
Two distinct, main receptor forms have been discovered, called ER-α and
ER-β respectively. They have different affinities for estradiol and different
anatomical distribution. For example only ER-α has been found in the liver, and
ER-β is the pre- dominant form in prostate. These differences may account, in
part, for the wide diversity of estrogen action in different tissues and under
different physiological and pathological states. It has been found, for
example, that in healthy ovarian tissue the β form predominates, but in ovarian
cancer the a form predominates. It is possible that the β form somehow
regulates the activity of the α form. The α and β forms have several nuclear
coactivators and repressors, and their activity depends also on their rates of
turnover.
Estrogen receptor antagonists have found a powerful use in the
prevention and treatment of breast cancer (see Clinical scenario above).
These compounds interfere with the processing of the normal intracellular
hormone–receptor interaction. This can occur at one or more of several sites
(Fig. 4d). The receptor itself may be blocked or post-receptor-binding events,
for example receptor dimerization, receptor turnover or mRNA or protein
synthesis, may be inhibited. Examples of estrogen receptor blockers are the SERMS
(selective estrogen receptor modulators) such as tamoxifen, raloxifene and
to remifene. These are interesting
because they appear to act as agonists in some tissues such as bone and liver
cells, and may therefore be important preventive measures for reducing the rate
of development of osteoporosis and for lowering blood cholesterol. SERMS may
act by activating as yet unidentified coactivators or corepressors and may
modulate estrogen receptor turnover. Their action may also be dictated by
whether they combine with ER-a or ER-b receptors.
Thyroid hormone receptors
Like other members of the nuclear receptor family, thyroid hormone
receptors function as hormone-activated transcription factors. In contrast to
steroid hormone receptors, however, thyroid hormone receptors bind to DNA in
the absence of hormone, leading usually to transcriptional repression. When
thyroid hormone binds to the receptor, however, it causes a conformational
change in the receptor that changes it to function as a transcriptional
activator. As with many other receptors, several isoforms have been discovered.
Currently, four different isoforms are recognized, namely: α-1, α-2, β-1 and
β-2. These different forms appear to be very important in development;
different isoforms are expressed at different stages of development and in
different organs and tissues. For example α-1, α-2 and βb-1 are expressed in
virtually all tissues in which thyroid hormones act, but β-2 is synthesized
mainly in the developing ear, and in the anterior pituitary gland and
hypothalamus. Receptor α-1 is the first isoform detected in the conceptus, and
the β form appears to be essential for normal brain development shortly after birth.
