Week 6 - Hormone-regulated Cancers Flashcards
What are nuclear hormone receptors
Receptors activated by steroids
Are transcription receptors (regulate expression of genes in our genome)
Receptor has 3 key domain:
1. Hormone binding domain (ligand)
2. DNA binding domain
3. Transcriptional Regulatory domain
- Receptors has an identified ligand
- when ligand binds to receptor conformation change occurs
- change allows receptor to bind to specifc DNA segments throughout the genome
- DNA binding leads to change in chromatin + recruitment of transcription machinery (to area)
- results in transcription starting at that site
Transcritpion is tightly regulated ~ disruptions can lead to cancers + metabolic disorders
NEED to have LIGAND BOUND before receptor exerts its effects
Transcription - process of copying a gene’s DNA sequence to make an RNA molecule
What are nuclear receptor ligands
Steroid hormone
Includes:
- Estradiol, Testosterone, Progeseterone, Oestrogen, Cortisol, Aldosterone
- ALL steroid hormones = all have similar structures
- Synthesised from cholesterol
What is the MoA and regulation of the activty of steroid receptors
ER = oestrogen receptor | PR = progesterone receptor
ALL Steroid Receptor has 3 key domains:
1. Hormone binding domain
- receptor won’t chang confomration unless steroid hormone (ligand) is bound to this
2. DNA binding domain
- without this receptor can’t bind to DNA
3. Transcriptional Regulatory domain
Steroid Receptor Activation
1. Steroid hormone binds to steroid receptor forming hormone-receptor complex
- HSP (heat shock proteins) are NEEDED as they stabilise the hormone to hormone receptor
- When HSP is removed hormone is released from receptor
- Binding causes conformational change
- change allows HRE (hormone response element) found on DNA to bind
3.Binding initiates transcription of target genes
- presence of HRE = transcription occurs
What is the MoA and regulation of the activity of Glucocorticoids in leukemia
GR = glucocorticoid receotor
GR is found in cytoplasm + regulates genes involved in development, metabolism + immune repsonse
- GR is found in almost all tissues
Glucocorticoids are hormones (ligands) bind to GR = Activated GR
GR is coupled with HSP
- HSP are released when ligand binds to GR
- GR is transolacted into nucleus once bound to ligand
- Bound / activated GR binds to HRE (on DNA) to begin transcription in nucleus
- Activated GR can inhibit other transcriptional complexes by remaining bound to HRE in nucleus (preventing them from binding to the HRE)
How can we treat Leukaemia
GR actiavtion can cause apoptosis
- USE GR agonists (synthetic) have stronger effect than natural ligand
- e.g. Dexamethasone ~ ‘induction therapy’
- drug induces apoptosis = kills leukaemic cells
- Activate Bim protein (is pro-apoptoic)
- this inhibits MCL-1 protein (which is pro-survival)
What is the MoA and regulation of the activity of Oestrogens in breast cancer
OR = oestrogen receptor | ERE = oestrogen response element
OR are found only in target tissue e.g. breast (not as widely expressed as GR)
Oestorogen is screted from ovaries, placenta, adrenal glands, adipose tissue
- has beneficial effects BUT ↑ plasma oestrogen levels = ↑ risk of breast (if homeostasis is disturbed)
- have ↓ expression in pre-menstural women
MoA:
- Oestrogen binds to OR = receptor goes through conformational change forming a dimer
- ERE (a HRE) on DNA binds to OR
- Stimultaes transcriptional activation or repression
- activation occurs only if bound to an activator (if bound to repressor = no transcription)
Breast Cancer:
- Has 5 diff. sub-types (have diff. biomarkers) which help identify best treatment for each patient
What is the MoA of SERMs (selective oestrogen receptor modulator)
SERMs = OR ligand | Stops oestrogen from binding to OR
SERMs are anti-oestrogen therapeutics
- bind to OR receptor causing confirmational change
- prevent oestrogen from binding to OR
- stops breast cancer BUT can cause malignant transformation in uterus
- e.g. when tamoxifen binds to receptor in uterine, it activates its receptor = ↑ risk of uterine cancer
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What happens if SERMs or Oestrogen drugs are given to OR negative patient
Cells can be OR positive or negative
- negative = has NO OR
- proliferation isn’t controlled by oesrtogen
= can’t be targeted with OR therapy as oestrogen (ligand) will have nothing to bind to
- positive = has OR
- proliferation controlled by oestrogen
= SERMs can inhibit breast cancer in OR positive patients ONLY
- Consider personalised therapy for each patient
What is the difference between Tamoxifen and Raloxifene
Both are SERMs + have ring structure
Tamoxifen:
- Metabolite of tamoxifen binds to OR = proliferation is inhibited
- 1 tablet daily for 5 YEARS
- once stop taking tablet effects last for 11 years
- Have small risk of developing endometrial cancer (ONLY whilst actively taking drug)
- more women get blood clots but less have chance of devloping cancer
Raloxifene:
- 1 tablet for 5 YEARS
- once stop taking effects last 2 years
- does NOT increase endometrial cancer risk
- less women get blood clots but more have chance of devloping cancer
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What is the MoA of Aromatase Inhibitors
Aromatase = enzyme that converts androgen to oestrogens
Causes oestrogen deprivation to achieve endocrine response in ER positive breast cancer
- haem protein group binds to androgenic substrate
- series of reactions which leads to formation of phenolic A-ring
Aromatase Inhibitors:
- Aromasin
- Arimidex
- Femara
- Aromatase is a CYP 450 enzyme
How does Faslodex work
It’s a SERD (selective oestrogen receptor degrader)
- Binds, blocks and degrades OR
= completely inhibits receptor signalling
An alternative to tamoxifen
Molecular basis of Androgen function
AR = androgen receptor
- 90% of testosterone is screted from testes + 10% from adrenal gland
- Testosterone can bind to DNA leading to cell proliferation
- testosterone enters cell + binds to AR
- causes dimerisation + conformational changes
- changes lead to DNA binding = transcriptional activation or repression
- will see an ↑ in PSA if prostate cancer cells are present
What are the biomarkers for prostate cancer
PSA = prostate specific antigen
-PSA is screened as a biomarker to diagnose if patient has prostate cancer
How do we target prostate cancer
- Eliminate testicular production of tetsosterone
- Supress hormones that lead to stimulation of testes
- i.e. GnRH, FSH, LH - Inhibit 5 alpha reductase
- converts / reduces testosterone into DHT - Block testoserone from binding to receptor
- using tamoxifen
How does LHRH Agonsists and anti-androgens treat prostate cancer
LHRH - Lutenising hormone releasing hormone
LHRH Agonist:
- stimulate the release of LH from anterior pituitary gland = ↑ testosterone production
- ↑ levels of testosterone activates negative feedback, downregulation of LH receptors = ↓ LH = ↓ testosterone
- NO testosterone = prostate cancer cells can’t grow = inhibition
- 1st gen = ↑ testosterone before ↓
- 2nd gen = injected SC act rapidly and inhibit release of LH (doesn’t ↑ testosterone first)
Anti-andrgoens:
- block testosterone from binding to androgen receptor by competitively binding to the receptor
- inhibits signalling pathway which stimulates growth of cancer cells
- 1st gen = compete with androgens for receptor
- 2nd gen = ↑ affinity for receptor + block receptor signalling
