Hormone receptor signalling and hormone therapies in prostate and breast cancer Flashcards
Where are hormones produced and what centers control this production?
Produced in the ovaries, testes, pancreas, adrenal gland, thyroid, adipose tissue. Production is controlled by the hypothalamus and the anterior pituitary gland.
How do hormones circulate in the blood?
Bound to globulins or albumin
How are sex hormones produced in men/women
Initiated by the Luteinizing hormone-releasing hormone (LHRH) released from the hypothalamus which induces the release of Luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary gland.
What organs produce testosterone?
Testes and to a lesser extent, the adrenal gland
What organs produce oestrogen>
The ovaries and to a lesser extent, adipose tissue
What role do oestrogen and testosterone both have in common?
They maintain bone density
How is testosterone produced in men?
LHRH released from the hypothalamus. Binds to pituitary gland receptors and induces the release of LH. LH binds to receptors on the testes which cause the production of testosterone. Adrenocorticotropic hormone (ACTH) will also lead to the production of testosterone.
What does testosterone do once it has been produced and secreted into the blood stream
Effects target cells which express the androgen receptor. It is a cytoplasmic receptor which, when bound by testosterone acts as a TF, translocating to the nucleus and inducing expression of a number of downstream target genes.
Where is the androgen receptor found in cells>
In the cytoplasm
What is a key target gene for testosterone when thinking about cancer
PSA
How is oestrogen produced in women.
LHRH induces secretion of LH and FSH from the pituitary. These bind to receptors on the ovary and induce the production of oestrogen. ACTH produced by the pituitary binds to the adrenal gland and causes the small release of oestrogen from adipose tissue.
What does oestrogen do once it has been produced by adipose tissue and the ovary
Binds to the cytoplasmic oestrogen receptor which acts as a TF when bound, translocating to the nucleus and initiating transcription of a number of target genes.
What is an important target gene for oestrogen
Cyclin D2, genes that are involved in the initiation of cell cycling.
What similarities do nuclear receptors have?
Their DNA binding domain and ligand binding domains have significant homology
What class of receptors do the oestrogen and androgen receptors fall into?
Nuclear receptors
What problems do the homology in DNA binding domains and ligand binding domains mean for hormone targeted therapies
DNA binding domain - Get rid of oestrogen or androgen receptor - another receptor might be upregulated to compensate for this loss and able to activate the same genes subsequently.
Ligand binding domain - small mutations in either eostrogen or androgen receptor ligand binding domains could let it accept a different ligand for activation of transcription
What are the transactivation domains?
A cytoplasmic and C terminal domain which are involved with co-regulators
What is important about the hinge region of nuclear receptors?
It contains the nuclear localisation signal. When exposed it induces translocation into the nucleus.
What protein do nuclear receptors bind to in the cytoplasm to confer stability?
Heat shock protein
What happens to the heat shock protein/ nuclear receptor complex following ligand binding?
Nuclear receptor dissociates from the heat shock protein and forms a dimer with another ligand bound nuclear receptor
What exposes the nuclear localisation signal (hinge region) of nuclear receptors?
Dimerisation of two ligand bound nuclear receptors.
What is the first step of the steroid biosynthesis pathway and what can be formed from this initial step.
- Cholesterol side chain is cleaved off to form pregnenolone. This can be used to form all the ligands of the nuclear receptor family
What enzymes are key in the production of steroid hormones and why?
- CYP17 - acts twice in the pathway with different effects. Used to form the androgens from progesterone and pregnenolone
CYP19A1/ Aromatase - forms oestrogens formed from testosterone and androstenedione
5alpha-reductase - Forms Dihydrotestosterone from testosterone
What is the strongest activator of the androgen receptor and how is this hormone produced.
Prostate cells contain the 5a-reductase enzyme which catalyses the production of dihydrotestosterone from testosterone. Dihydrotestosterone is the most potent activator of the androgen receptor
How is testosterone produced in the testes?
LH binds to a plasma membrane receptor in Leydig cells, a signalling cascade leads to cholesterol being shuttled into the mitochondria. Cholesterol is converted to prognenolone via CYP17. Prognenolone diffuses out of the mitochondria and into the smooth ER where the rest of the biosythesis pathway takes place to produce testosterone; which will diffuse into the blood.
How is oestrogen produced in the ovaries?
LH binds to a plasma membrane receptor in Theca cells in the follicle. A subsequent signalling cascade will produce androstenedione from cholsterol. Androstenedione then enters the granulosa cell by diffusion. If the granulosa cell has been stimulated by FSH on FSHR then there is an upregulation of aromatase. This converts androstenedione to oestrogen. Oestradiol is the form of oestrogen that is released into the blood.
In what adrenal cortex zone is testosterone produced and why is this the case?
Zona reticularis because it expresses CYP17A and b5 co-regulator which are required for the production of testosterone.
What percentage of breast cancers are hormone receptor positive?
70%
What three things are important for deciding which therapy to give to a breast cancer patient?
- Tumour expression of ER, PR and HER2 (HER2 positive won’t receive hormonal therapy)
- The patients menopausal state
- If the disease is non-invasive, primary, locally advanced or metastatic.
What drug is given to post-menopausal women positive for ER and early stage breast cancer?
Radiotherapy followed by aromatase inhibitors
What drug is given to premenopausal women positive for ER and early stage breast cancer?
Tamoxifen with or without ovarian ablation/suppression
What is given to higher risk patients before hormone therapy compared to lower risk patients?
Chemotherapy
What method is used to block androgen synthesis by ovarian suppression?
Use of LHRH agonists. Flooding the pituitary gland with LHRH will lead to the removal of LHRH receptors. There is initially a surge in oestrogen levels which induces a tumour flare but this is followed by a decline in the amount of oestrogen produced.
What is an FDA approved LHRH analogue used to treat premenopausal breast and prostate cancer and what is the main benefit of this drug?
Goserelin - major advantage is their potential reversibility. This reduces the risk of osteoporosis and premature coronary artery disease. Potentially preserves future fertility.
How do aromatase inhibitors prevent the production of oestrogen in postmenopausal women
Only production of oestrogen is via the aromatisation of androgens by aromatase enzymes in adipose tissue. Aromatase inhibitors prevent this production.
What is an example of an aromatase inhibitor?
Anastrazole, Letrozole, Vorozole
How does tamoxifen inhibit the oestrogen receptor?
Non-steroidal ER ligand. Causes an off-state of the ER receptor specifically in breast cancer tissue (likely dependent on co-factors that ER interacts with to initiate transcription).
What is fulversterant and when is it used?
A selective oestrogen receptor degrader by inhibiting the dimerization and nuclear translocation into the nucleus. It’s used mainly when tamoxifen and aromatase inhibitors have stopped working and in metastatic breast cancer patients.
What are GDC-0927, AZD9496 and Bazedoxifen?
Novel fulvesterent-like drugs with better bioavailibility
How do breast cancer patients become resistant to hormonal treatments?
ESR1 mutations found in ligand binding domain, GOF function mutations cause ligand independent activity.
What drug is able to improve survival in patients that have developed an ESR1 mutation?
Fulvestrant
What is the standard first-line treatment in patients with advanced prostate cancer?
LHRH agonists (Goserelin) which shuts down the production of LH after an initial flare.
How is the tumour flare induced by Goserelin prevented in prostate cancer patients?
Co-treatment with anti-androgens
What is Degarelix?
A LHRH antagonist, avoids the flare seen in LHRH agonists
What is Bicalutamide? Whats the problem with it?
An antiandrogen which blocks the androgen receptor - problem with first generation of antiandrogens is that mutations in the ligand binding domain of androgen receptor caused the antagonist drug to become an agonist for the receptor.
What is enzalutamide?
A second generation androgen receptor antagonist. It has a stronger binding affinity and acts differently by blocking the translocation of the receptor to the nucleus
How has the enzalutamide drug been improved?
Apalutamide - less able to cross the blood brain barrier so reduces the chances of seizures that was seen with enzalutamide.
What is Abiraterone?
A CYP17 inhibitor
How do prostate cancer patients become resistant to therapy?
Amplification/ mutation of the AR gene.
splice variant of AR gene which lacks a ligand binding domain so it is active in the absence of ligand.
How does the AR L702H mutation confer resistance to treatment?
If treated with prednisone (a steroid given in combination with abiraterone or taxanes) then this mutation makes the androgen receptor receptive to prednisone and will become highly proliferative.
