molecular basis of endocrine therapy Flashcards
Give examples of steroid hormones.
Oestrogens, androgens, glucocorticoids.
What is the process of oestrogen production from cholesterol?
Cholesterol to pregnenolone to progestagens, to androgens, to oestrogens.
How are androgens converted to oestrogens?
Via a process called aromatisation by the P450 aromatase enzyme.
How is oestrogen production regulated in premenopausal women?
A signal from the hypothalamus releases leutinising hormone - releasing hormone (LHRH) to the pituitary gland, which causes release of leutinising hormone (LH) and follicle stimulating hormone (FSH) from the pituitary. These hormones act on the ovary causing oestrogen production in the follicular cells via aromatisation of androgens.
Where is the primary oestrogen production in postmenopausal women?
In postmenopausal women, the primary source of oestrogens is via aromatisation in peripheral tissues, e.g. adipose tissue or in the adrenal gland.
How does oestrogen act at the oestrogen receptor?
As oestrogens are small, hydrophobic molecules, they can diffuse freely into target cells to reach the nucleus. At the nucleus they can interact with the high affinity receptor, to cause the chaperone proteins (hsp90, hsp70, and cyc40) to dissociate, allowing the receptors to dimerise. This causes recruitment of co-activator proteins and a polymerase complex which interacts with DNA at the specific oestrogen responsive element, causing transcription of the target gene.
What is the structure of oestrogen receptor (alpha)
This receptor contains a DNA binding domain, a ligand binding domain, a dimerisation domain. Other domains are present but less important.
How is oestrogen ligand able to bind to the oestrogen receptor alpha?
The ligand binding domain portion of the receptor consists of 3 anti-parallel layers of helices which create a hydrophobic pocket for oestrogen to bind. When the ligand is in the hydrophobic pocket, the conformation is stabilised and residues are folded across, exposing amino acid residues for co-activators to bind.
How does the oestrogen receptor interact with DNA?
The receptor binds via the DNA binding domain. There are 2 zinc binding domains which interact with cysteine molecules to produce 2 zinc fingers linked by a flexible linker. This contains the recognition helix which allows recognition of the DNA after dimerisation of the DNA binding domains.
How can you determine ER+ tumour types?
Expression of ER is a marker used to assess response to endocrine therapies. Immunohistochemistry is used to identify ER expression. The proportion of cells expressing ER and the intensity of expression is combined to give an Allred score. An Allred score of 3+ is determined as ER+, however 6-8 is considered a market for greater response rate.
What other markers could we use to determine endocrine therapy response?
TFF3 has recently been identified as a potential marker for response to endocrine therapy (FEB May, 2015). TFF3 has been identified as higher in tumours who responded to endocrine therapy, therefore this may be incorporated in future studies as ER overexpression is an imperfect marker. Progresterone receptor expression should also be utilised alongside ER expression, as progresterone is induced by oestrogen, e.g. a study found that when PgR+ and ER+ tumours were given endocrine therapy, they have a 75-80% response rate, in comparison to the 40% response rate seen with tumours only ER+.
What is Tamoxifen? How does it work? How effective is it? Who is it administered to?
Tamoxifen is a small molecule drug which blocks oestrogen from binding to its receptor. Tamoxifen its metabolised to hydroxytamoxifen and it binds in the hydrophobic pocket of the ligand bindign domain where oestrogen usually binds. It has anti-oestrogenic activity in the breast and brain (can cause hot flushes). It is given to premenopausal and post-menopausal patients. However, more recent evidence suggests that postmenopausal women should ideally be given aromatase inhibitors as first-line treatment, as long term effects are much less severe.
What other drugs might be given following Tamoxifen failure?
If Tamoxifen fails, there is Fulvestrant which also binds to ER and initiates its degradation. It is used as a second line therapy as it must be given intramuscularly which is not pleasant for the patient. Pre-menopausal patients may also be offered Zoladex, which is an agonist for LHRH, therefore prevents LH secretion. Otherwise, post-menopausal patients may be given aromatase inhibitors.
What are the types of aromatase inhibitors?
Type 1 steroidal inhibitors compete with androgens binding to the P450 aromatase enzyme, therefore inhibit the activity. These bind irreversibly, e.g. exemestane. Type 2 steroidal inhibitors bind reversibly to the aromatase enzyme to inhibit the activity, e.g. anastrazole.
Why is chemotherapy or surgical oophorectomy not preferred in premenopausal women?
Surgical oophorectomy involves the surgical removal of the ovaries. This is often not preferred in premenopausal women as it is a permanent procedure which induces early menopause and prevent pregnancy. Cytotoxic chemotherapy is less direct, however can cause ovarian dysfunction, leading to the same side effects specified above.
