Signalling

Question 1

Describe steroid hormone receptors

Answer 1

Ligand-dependent transcription factors

Question 2

Describe ERalpha mediated regulation of transcription

Answer 2

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

Question 3

Describe ER function

Answer 3

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

Question 4

List breast cancer risk factors

Answer 4

Lifetime oestrogen exposure
Time of first pregnancy
Physical activity
Obesity
Breast feeding
Environment

Question 5

Why is obesity a risk factor in breast cancer?

Answer 5

Adipose tissue express aromatase, converting androgens to oestrogens

Question 6

Describe oestradiol (E2) synthesis and function

Answer 6

Synthesised in the ovaries
Regulated by other hormones FSH and LH
These hormones can be manipulated to subsequently manipulate E2 production

Question 7

What are good effects of oestrogen action?

Answer 7

Maintaining bone, sexual function
Cardiovascular protection
Protecting brain function
Protecting against colorectal cancer

Question 8

What are bad effects of oestrogen action?

Answer 8

Promote proliferation of mammary epithelial and endometrial epithelial

Question 9

Describe breast cancer hormonal therapy

Answer 9

Majority of breast cancers rely on E2 for growth

Therapies aim to ablate E2 action: SERMs, aromatase inhibitors, sulfatase inhibitors

Question 10

How does E2 differ in pre and post menopausal women?

Answer 10

Pre: ovaries produce majority
Post: made locally
Pre: treated with SERMs
Post: treated with SERMs and AIs

Question 11

What is tamoxifen?

Answer 11

Antagonist in breast cancer but an agonist in uterus. Steroid receptor co-activator 1 is higher in uterus than in breast

Question 12

What effects the mechanism of SERMs?

Answer 12

Ratio of receptor co-activators to co-repressors

Question 13

What is raloxifene?

Answer 13

Antagonist in breast and uterus. Raloxifene has different conformational effects on the ER and recruits more co-repressors

Question 14

How can we target oestrogen metabolism?

Answer 14

Aromatase inhibitors
Sulphatase inhibitors
More tumours have sulphatase activity than aromatase
Experimentally investigating 17betaHSD
inhibition
Can combine both treatments

Question 15

Give examples of aromatase inhibitors

Answer 15

Letrozole

Anastrazole

Question 16

Give examples of sulphatase inhibitors

Answer 16

Irasostat

STX213

Question 17

What treatments are available for prostate cancer?

Answer 17

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

Question 18

How do anti-androgens work?

Answer 18

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

Question 19

What is abiraterone?

Answer 19

An inhibitor of 17alpha hydroxylase
Stops formation of precursors
Also causes renal disruption by blocking aldosterone

Question 20

What is targeted in leukaemia treatment?

Answer 20

Glucocorticoid receptors