intro to hormone dependent cancers

Question 1

define hormone

Answer 1

chemical messenger made by specialist cells, usually within endocrine glands and released into bloodstream to have an effect in another part of the body

Question 2

where are hormones produced

Answer 2

pineal gland
hypothalamus 
pituitary 
thyroid 
pancreas
adrenal cortex 
testes/ovaries

Question 3

3 main types of hormones

Answer 3

steroids = lipid soluble small molecules
peptide
modified amino acids

Question 4

describe steroid hormones

Answer 4

all synthesised from cholesterol
basic 4 ring steroid backbone structure
adrenal cortex = synthesises corticosteroids and mineralcorticosteroids
e.g androgen, testosterone, estradiol
work systemically, have effect on several tissues
females oestrogen
male testosterone

Question 5

describe sex hormones

Answer 5

responsible for sexual dimorphism between males and females

development of secondary sexual characteristics e.g growth spurt/body hair

Question 6

key characteristics of nuclear receptors

Answer 6

1. ligand binding domain = binds specific steroid molecules with high affinity
2. DNA binding domain = binds specific DNA sequences
3. activation function domain = recruits gene activation machinery, some receptors have secondary AF2 domain towards C-terminal

Question 7

describe ligand activated TFs

Answer 7

1. ligand binding to LBS = stiff in alpha helix = activates receptor
2. receptor dimerises, moves into nucleus and binds specific DNA sequences
3. receptor recruits DNA modifying enzymes e.g. histone deacetylases

Question 8

describe DNA binding domain

Answer 8

contains 2 zinc finger domains, essential for sequence specific DNA binding

1. CL zinc finger = specific DNA sequence binding
2. cll zinc finger = interaction with DNA phosphate backbone

Question 9

hormone responsive genes

Answer 9

genes may be upregulated by steroid hormone receptor
some genes may be downregulated
genes include functional tissue specific genes, cell cycle, proliferation genes, gene involved in tissue development and differentiation

Question 10

what are hormone response elements

Answer 10

specific DNA sequences found in promoters of hormone responsive genes. many are palindromic

Question 11

describe nuclear receptor family

Answer 11

48 nuclear receptor genes
share common domain structure and arise from common evolutionary ancestors
share structure that is activated by ligand binding

Question 12

describe the breast

Answer 12

apocrine gland, produces milk
milk producing part = 15-20 sections = lobes
within lobes = lobules where milk is produced
milk travels through ducts

Question 13

apocrine gland

Answer 13

exocrine gland = secretes substances out
endocrine = secretes substances directly to bloodstream
apocrine = specialised exocrine gland, cell cytoplasm
breaks of releasing contents

Question 14

describe mammary gland tissue structure

Answer 14

2 compartments
- luminal = single layer of polarised epithelium around ductal lumen, luminal cells produce milk during lactation

basal = cells that don’t touch lumen basally orientated myoepithelial cells in contact with basement membrane, have contractile function during lactation

Question 15

describe 2 major phases during mammary gland development

Answer 15

1. hormone independent from embryonic development up to puberty
2. hormone dependent during puberty, menstrual cycle and pregnancy

Question 16

what does oestrogen do in adults

Answer 16

allows maintenance of mammary gland tissue and primes tissue for effects of progesterone during pregnancy for milk production

Question 17

describe breast cancer

Answer 17

when abnormal cells in breast begin to grow and divide in uncontrolled way and form a tumour

begins in breast tissue, in cells that line milk ducts of breast
1/8 women develop breast cancer in their lifetime
main risks = age, lifestyle, genetic familial factors
taking hormones/hormone replacement during menopause can increase risk

Question 18

describe ductal breast carcinoma in situ

Answer 18

cancer cells develop within ducts of breast but remain within ducts
cancer cell hasn’t developed ability to spread outside ducts into surrounding breast tissue

Question 19

describe lobular breast carcinoma in situ

Answer 19

uncommon condition in which abnormal cells form in milk glands of breast = either ER positive or negative
majority of breast cancer develops from luminal cells = express ER+ve have good prognosis
if negative = poor prognosis

Question 20

explain ER in breast cancer

Answer 20

ER controls cell proliferation/development and differentiation in highly controlled manner

in breast cancer = ER pathway becomes uncontrolled and no longer able to bind to dna/open chromating
ER governs cancer cell proliferation, controls and influences genes involved in metastasis, invasion and adhesion
switch off ER signalling = switch off cancer growth

Question 21

inhibiting estrogen action - how?

Answer 21

blocking estrogen competitively binding to receptor and degrading ER protein
no ER signalling = no breast cancer cell growth

Question 22

fulvestrant

Answer 22

analogue of estradiol
competitively inhibits binding of estradiol to ER, with binding affinity that is 89% of estradiol
fulvestrant = ER binding impairs receptor dimerisation = blocks nuclear localization of receptor
fulvestrant = ER complex in nucleus = transcriptionally inactive as AF1/2 are disabled

Question 23

tamoxifen

Answer 23

binds ER at ligand binding site
partial agonist but does not cause full activation of ER
has mixed activity = activates ER in uterus and liver, acts as antagonist in breast tissue
is a selective estrogen receptor modulator

Question 24

describe aromatase inhibitors

Answer 24

ovaries no longer functional in post menopausal women = source of estrogen comes from peripheral conversion of androgens by aromatase enzyme

present in multiple organs incl adipose tissue/brain tissue/blood vessels
androgens are hormones e.g testosterone/adrenal androgens

Question 25

describe types of aromatase inhibitors

Answer 25

type 1 = androgen analogues bind irreversibly to aromatase = suicide inhibitors. the duration depends on rate of de novo synthesis of aromatase

type 2 = contain functional group within the ring that binds heme iron of cytochrome p450, interfering with hydroxylation reactions

Question 26

describe prostate cancer

Answer 26

most common cancer in males 
prostate = produce prostatic fluid that creates semen when mixed with sperm produced by testes 
located just underneath bladder 
prostate = exocrine gland 
gene = BRAC1/pTen
symptoms 
-frequent urination 
- poor urinary stream 
- urgent need to urinate 
- lower back pain 
- blood in urine

Question 27

3 ways to detect prostate cancer

Answer 27

1. digital rectal examination
2. PSA test
3. ultrasound

Question 28

prostate cancer treatment

Answer 28

waiting = low grade tumour, older patients
radical prostatectomy = stage T1/2
radical radiotherapy = external up to T3, internal implants
hormone therapy = prostatectomy/radical radiotherapy

Question 29

risk factors of prostate cancer

Answer 29

age
race/ethnicity = more common in black men
geography
family history

Question 30

describe genes in prostate cancer

Answer 30

pten = phosphate that antagonises phosphatidylinositol 3-kinase signalling pathway
loss of pTen = increased growth factor signalling

TMPRSS2-ERG fusion = most frequent, present in 40-80% of prostate cancers in humans

Question 31

describe androgen receptor signalling

Answer 31

AR located in cytoplasm and many chaperone proteins
testosterone converted to potent agonst and crosses into prostate = dihydrotestosterone binds the AR
AR binds coactivator recruitment
switch off AR signalling and cancer growth

Question 32

describe inhibition of testosterone synthesis

Answer 32

androgens circulate blood, converted to testosterone in testes
testosterone circulates blood and reaches target organs
adrenal androgen production can be inhibited = deprives testes of testosterone precursors

Question 33

describe control of hormone production

Answer 33

suppression of GnRH and LH
goserelin = super agonist
abarelix = antagonist