Signalling Flashcards
Describe steroid hormone receptors
Ligand-dependent transcription factors
Describe ERalpha mediated regulation of transcription
Oestradiol (E2) enters the cytoplasm, ERalpha in the cytoplasm bound to HSP90. Binding of E2 to ERalpha causes loss of HSP90. Receptor-ligand enter nucleus
Dimerise
Complexes (with LSD1) removes histone methyl transferase and relaxes chromatin
Allows RNA polymerase II to work
Can also recruit HDAC to close the chromatin
Describe ER function
ER alpha, beta and gamma variants All G protein coupled receptors ERa is pro proliferative ERb is pro apoptotic Role in breast cancer 15-25% of breast cells express ER
List breast cancer risk factors
Lifetime oestrogen exposure Time of first pregnancy Physical activity Obesity Breast feeding Environment
Why is obesity a risk factor in breast cancer?
Adipose tissue express aromatase, converting androgens to oestrogens
Describe oestradiol (E2) synthesis and function
Synthesised in the ovaries
Regulated by other hormones FSH and LH
These hormones can be manipulated to subsequently manipulate E2 production
What are good effects of oestrogen action?
Maintaining bone, sexual function
Cardiovascular protection
Protecting brain function
Protecting against colorectal cancer
What are bad effects of oestrogen action?
Promote proliferation of mammary epithelial and endometrial epithelial
Describe breast cancer hormonal therapy
Majority of breast cancers rely on E2 for growth
Therapies aim to ablate E2 action: SERMs, aromatase inhibitors, sulfatase inhibitors
How does E2 differ in pre and post menopausal women?
Pre: ovaries produce majority
Post: made locally
Pre: treated with SERMs
Post: treated with SERMs and AIs
What is tamoxifen?
Antagonist in breast cancer but an agonist in uterus. Steroid receptor co-activator 1 is higher in uterus than in breast
What effects the mechanism of SERMs?
Ratio of receptor co-activators to co-repressors
What is raloxifene?
Antagonist in breast and uterus. Raloxifene has different conformational effects on the ER and recruits more co-repressors
How can we target oestrogen metabolism?
Aromatase inhibitors Sulphatase inhibitors More tumours have sulphatase activity than aromatase Experimentally investigating 17betaHSD inhibition Can combine both treatments
Give examples of aromatase inhibitors
Letrozole
Anastrazole
Give examples of sulphatase inhibitors
Irasostat
STX213
What treatments are available for prostate cancer?
Orchiectomy
Diethylstilbestrol - stops LH production by the pituitary
LHRH agonist - eg. cetrorelix, ganirelix
Causes internalised GnRH. Initial flare of LH and FSH followed by a fall
Anti-androgens - eg. flutamide
How do anti-androgens work?
Bind the AR and inhibit its activity.
AR resistance can develop
Possibly due to an increase in co-activators or decrease in co-repressors, increasing sensitivity
Prostate cells can become androgen independent. Palliative chemotherapy offered
What is abiraterone?
An inhibitor of 17alpha hydroxylase
Stops formation of precursors
Also causes renal disruption by blocking aldosterone
What is targeted in leukaemia treatment?
Glucocorticoid receptors
