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