Androgen receptors

Question 1

How does the androgen receptor function?

Answer 1

• resides in the cytoplasm when not associated with androgen
• upon ligand binding inhibitory chaperones are dissociated and AR moves to the nucleus
• AR undergoes homo-dimerization and binds to the androgen responsive elements of the DNA
• recruits co-activators and gene expression occurs

Question 2

What are the two basic approaches to reduce testosterone?

Answer 2

• surgical orchiectomy or medical castration (e.g. leuprolide)
• block receptor activity with an anti-androgen (e.g. bicalutamide)

Question 3

What are the three main sources of androgen in prostate cancer?

Answer 3

• testis (90-95%)
• adrenal glands (5-10%)
• intracrine androgen production (in the prostate cells themselves)

Question 4

What is the action of flutamide and bicalutamide for treatment of prostate cancer?

Answer 4

likely via association of these anti-androgens with the AR’s ligand binding domain

Question 5

What are the mechanisms of resistance to hormone therapy in PCA (prostate cancer)?

Answer 5

• AR activation via non-gonadal testosterone
• over expression of androgen receptor (AR)
• AR mutation leading to promiscuous AR activation
• truncated form of AR, with constitutive activation in the ligand binding domain

Question 6

What enzyme plays a key role in testosterone production?

Answer 6

CYP17

Question 7

How does abiraterone lower testosterone?

Answer 7

by blocking CYP17

side effects due to excess of precursor, pregnenolone, a mineralcortacoid

Question 8

What is the mechanism of action of enzalutamide?

Answer 8

• inhibits nuclear translocation of androgen receptor (AR)
• inhibits co-activator recruitment
• inhibits DNA binding of AR