Breast and prostate cancer

Question 1

What are all steroid hormones synthesised from

Answer 1

Cholesterol

Question 2

What is the the link between steroid hormones and breast/ prostate cancer

Answer 2

the steroid hormones can still influence the growth and development. The dependence of these tissues on steroid can be exploited and used as an anti-cancer therapy.

Question 3

Steroid hormone action

Answer 3

–Steroid hormones cross into the cell ( due to its lipophilic structure) cytoplasm where
they will bind to their receptor
–Binding to the receptor causes a conformational
change in the nuclear receptor, causing it to become
activated (some nuclear receptor dimerise at this
point)
–Nuclear receptors then translocate into the nucleus
–Nuclear receptors bind to specific DNA sequences
called response elements located in the promoters of
steroid responsive genes.
–Steroid responsive genes are switched on and
upregulated.

Question 4

what are the 3 key characteristics of nuclear receptors

Answer 4

Ligand binding domain (LBD) 
----Binds specific steroid molecules with high 
affinity 
DNA binding domain (DBD) 
----Binds specific DNA sequences 
Activation function domain (AFI & 2) 
----Recruits gene activation machinery

Question 5

Steps in Ligand Activated Transcription Factors

Answer 5

1. Ligand binding to the ligand binding site
   causes a shift in an a—helix, activating the
   receptor.
2. Receptor dimerises, moves into the nucleus
   and binds to specific DNA sequences
3. Receptor then recruits DNA modifying
   enzymes e.g. histone deacetylases, other
   transcription factors and RNA polymerase to
   promoters of hormone responsive genes.

Question 6

what does the DNA binding domain contain which helps with specific DNA binding and interaction

Answer 6

The DNA binding domain contains 2 zinc fingers domains, which are essential for sequence specific DNA binding.

-Cl Zinc finger
Specific DNA
sequence binding

-Cll Zinc finger
Interaction with the
DNA phosphate backbone

Question 7

what are hormone response elements

Answer 7

Hormone Response Elements are specific DNA sequences
found in the promoters of hormone responsive genes.
Many are palindromic

Question 8

how many nuclear receptor genes are in humans

Answer 8

48

Question 9

similarity of steroid receptors

Answer 9

Receptors have a high homology in the DNA binding domain, and differ in ligand binding
domains, and differ significantly in N-terminal activation domains

Question 10

what are the main five steroid receptors , their abbreviation and respective ligands

Answer 10

1) Oestrogen Receptor (ER)- oestradiol, estrone, estriol
2) Androgen Receptor (AR)- androstenedione, testosterone, dihydrotestosterone
3) Progesterone Receptor (PR)- progesterone, pregnenolone
4) Glucocorticoid Receptor (GR) -cortisol and cortisone
5) Mineralocorticoid Receptor (MR) -aldosterone

Question 11

What kind of gland is the breast

Answer 11

specialised form of exocrine gland called Apocrine gland

Question 12

the milk producing part of the breast is organised into how many section and what are they called

Answer 12

15-20

lobes

Question 13

what are the structures within each lobes called

Answer 13

lobules

Question 14

what are the 2 cell compartment in the mammary epithelium

Answer 14

• Luminal — form a single layer of polarized epithelium around the ductal lumen, luminal cells produce milk during lactation.
• Basal — comprise of the cells that do not touch the lumen, basally oriented myoepithelial cells in contact with the basement membrane, have contractile function during lactation

Question 15

What is the function of ER in the normal breast tissue

Answer 15

• Oestrogen, together with other hormones (e.g. growth hormone and cortisol) drives the expression of genes involved in cellular proliferation and differentiation
• In the adult oestrogen allows for the maintenance of mammary gland tissue, and also primes the tissue for the effects of progesterone during pregnancy for milk production.

Question 16

what is the progesterone activity in the normal breast

Answer 16

• The progesterone receptor gene is switched on by the oestrogen receptor
• Progesterone increases the branching of the ducts
• Prolonged progesterone receptor activity i.e. during pregnancy, leads to more side branching and lactogenic differentiation (together with prolactin hormone).

Question 17

what are some of the risk factors to breast cancer

Answer 17

-Age - The risk for breast cancer increases with age; most breast cancers are diagnosed after age 50.
-Genetic mutations to certain genes, such as BRCAI and BRCA2.
• Reproductive history. Early onset of menstrual cycle before 12yrs and starting menopause after 55yrs expose women longer to hormones.
• Previous treatment using radiation therapy to the chest or breasts (e.g. treatment for lymphoma) before age 30 have a higher risk of getting breast
cancer later in life.
-not being physically active
-overweight or obesity
taking hormones or contraceptive pills
-alcohol

Question 18

Ductal breast carcinoma in situ (DCIS)

Answer 18

Cancer cells develop within the ducts of the breast but remains within the ducts- have not gained the ability to spread

Question 19

Lobular Breast Carcinoma in Situ (LCIS)

Answer 19

Lobular carcinoma in situ (LCIS) is an 
uncommon condition in which abnormal 
cells form in the milk glands (lobules) in 
the breast. 
LCIS isn't cancer. But being diagnosed 
with LCIS indicates that there could be an 
increased risk of developing breast 
cancer.

Question 20

where does the majority of breast cancer arise

Answer 20

luminal cells, these cells express ER

Question 21

ER positive and negative breast cancer

Answer 21

The majority of breast cancers are ER positive and have a good prognosis, however the remainder are ER-ve and
have a relatively poor prognosis.
ER-ve breast cancers cannot be treated ‘hormonally’ and patients are given more conventional therapies.

Question 22

what is fulvestrant

Answer 22

aka faslodex
is an analogue of oestradiol, which competitively inhibits binding of oestradiol to the ER

• Fulvestrant — ER binding impairs receptor dimerisation, and
energy-dependent nucleo-cytoplasmic shuttling, thereby
blocking nuclear localisation of the receptor.
• Additionally, any fulvestrant— ER complex that enters the
nucleus is transcriptionally inactive because both AFI and AF2
are disabled.
• The fulvestrant—ER complex is unstable, resulting in
accelerated degradation of the ER protein.

Question 23

What Tamoxifen

Answer 23

Tamoxifen binds the ER at the ligand binding site.
Tamoxifen is a partial agonist but does not cause the full activation of ER.
It has a mixed activity— it activates ER in the uterus and liver, but acts as an antagonist in breast tissue.
Tamoxifen is a Selective Estrogen Receptor Modulator (SERM).
Tamoxifen bound ER does not fold properly and the AF2 domains do not function

Question 24

Aromatase inhibitors (what are the 2 types)

Answer 24

Type 1 inhibitors, like exemestane, are
androgen analogues and bind irreversibly to aromatase, so
they are also called “suicide inhibitors”. The duration of
inhibitory effect is primarily dependent on the rate of de
novo synthesis of aromatase.
Type 2 inhibitors, like anastrozole, contain a
functional group within the ring structure that binds the
heme iron of the cytochrome P450, interfering with the
hydroxylation reactions.

Question 25

what kind gland is the prostate

Answer 25

a specialised type of exocrine gland, called apocrine gland

Question 26

where does prostate cancer start

Answer 26

it originates in the cells that line the lumen. These are the luminal epithelial cells. first they will hyper proliferate forming prostatic intraperitoneal neoplasia(PIN) and the they become invasive adenocarcinoma

Question 27

what are the 3 tests done to detect prostate cancer

Answer 27

1) digital rectal examination (DRE)-most commonly done
2) PSA test
3) ultrasound

Question 28

What does TNM classification of prostate cancer stand for

Answer 28

T = size and extend of tumour 
N = number of lymph nodes involved
M= if it has metastasised

Question 29

How many stages are in T and what are they

Answer 29

4
T1= small and localised tumour 
T2= palpable tumour 
T3= escape from prostate gland 
T4= local spread to pelvic region

Question 30

numbering and meaning of N

Answer 30

N0=No cancer cells found in any lymph nodes
N1= 1 positive lymph node < 2cm across
N2=positive lymph node or 1 between 2-5cm across
N3= Any positive lymph node > 5 cm across

Question 31

numbering and meaning of M

Answer 31

M1a= Non-regional lymph nodes 
M1b= Bone 
M1c= Other sites

Question 32

what are the 4 prostate cancer treatment

Answer 32

Prostate cancer treatments
• “Watchful waiting” =Low grade tumour, older patients
• Radical prostatectomy = Stage Tl or T 2 (confined to prostate gland)
• Radical radiotherapy = External up to T 3 (spread past capsule)
Internal implants (brachytherapy) for Tl/2
• Hormone therapy =± prostatectomy or radical radiotherapy
Metastatic prostate cancer

Question 33

what is PTen

Answer 33

-PTEN is a phosphatase that antagonizes the phosphatidylinositol 3-kinase signalling pathway. which normally leads cell growth
-As P TEN is the only known 3’ phosphatase counteracting the
P13K/AKT pathway.
Loss of P Ten results in increased
growth factor signalling.

Question 34

which gene fusion is frequent in prostate cancer

Answer 34

TMPRSS2-ERG fusion

Question 35

Androgen Receptor (AR) signalling

Answer 35

AR is located in the cytoplasm associated with
many chaperone proteins.
Testosterone is converted to a more potent agonist as it crosses into the prostate Dihydrotestosterone (DHT) then binds the AR

Question 36

how does the process go from cholesterol to cell growth

Answer 36

cholesterol - testosterone- DHT- AR binding -AR translocation- AR DNA binding - AR co-factor recruitment - AR transactivation- Cell growth

Question 37

What is used to inhibit androgen synthesis

Answer 37

Abiraterone acetate (ZYTIGA)

Question 38

what are the names of the super agonist and antagonist used to depress testosterone production in the testes

Answer 38

Goserelin- super agonist

Abarelix - Antagonist

Question 39

what is used to inhibit the conversion from testosterone to DHT

Answer 39

5alpha-reductase inhibitors( finasteride and dutasteride)

Question 40

what is used to prevent androgen binding to its receptor

Answer 40

competitive anti-androgen ( Bicalutamide, Enzalutamide, Flutamide, Nilutamide)

Question 41

what are the 8 methods by which resistance can occur in prostate cancer treatment

Answer 41

• Some breast and prostate advanced tumour start to synthesise their own steroid hormones.
• Ligand binding site mutations make the receptors promiscuous
• Signal amplification, and increased sensitivity to low hormone levels

-Cross over with other signal pathways e.g. growth factors can
phosphorylate and activate receptors
— Prevalent for breast cancers

-Androgen Receptor transcript variants: activation in the absence of ligand e.g. AR-variant7 (VI) -Truncated AR without
C terminus -Active without ligand in prostate cancer

• receptor bypass
• Receptor cofactor amplification -Cofactor amplification can amplify the signal from steroid receptors in response to a low level of steroid hormone.

-Antagonists become agonists via LBD mutations -Antagonists used for prostate cancer treatment can become potent
activators of a mutant androgen receptor.