Breast and prostate cancer Flashcards
What are all steroid hormones synthesised from
Cholesterol
What is the the link between steroid hormones and breast/ prostate cancer
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.
Steroid hormone action
–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.
what are the 3 key characteristics of nuclear receptors
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
Steps in Ligand Activated Transcription Factors
- Ligand binding to the ligand binding site
causes a shift in an a—helix, activating the
receptor. - Receptor dimerises, moves into the nucleus
and binds to specific DNA sequences - Receptor then recruits DNA modifying
enzymes e.g. histone deacetylases, other
transcription factors and RNA polymerase to
promoters of hormone responsive genes.
what does the DNA binding domain contain which helps with specific DNA binding and interaction
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
what are hormone response elements
Hormone Response Elements are specific DNA sequences
found in the promoters of hormone responsive genes.
Many are palindromic
how many nuclear receptor genes are in humans
48
similarity of steroid receptors
Receptors have a high homology in the DNA binding domain, and differ in ligand binding
domains, and differ significantly in N-terminal activation domains
what are the main five steroid receptors , their abbreviation and respective ligands
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
What kind of gland is the breast
specialised form of exocrine gland called Apocrine gland
the milk producing part of the breast is organised into how many section and what are they called
15-20
lobes
what are the structures within each lobes called
lobules
what are the 2 cell compartment in the mammary epithelium
- 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
What is the function of ER in the normal breast tissue
- 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.
what is the progesterone activity in the normal breast
- 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).
what are some of the risk factors to breast cancer
-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
Ductal breast carcinoma in situ (DCIS)
Cancer cells develop within the ducts of the breast but remains within the ducts- have not gained the ability to spread
Lobular Breast Carcinoma in Situ (LCIS)
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.
where does the majority of breast cancer arise
luminal cells, these cells express ER
ER positive and negative breast cancer
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.
what is fulvestrant
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.
What Tamoxifen
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
Aromatase inhibitors (what are the 2 types)
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.
what kind gland is the prostate
a specialised type of exocrine gland, called apocrine gland
where does prostate cancer start
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
what are the 3 tests done to detect prostate cancer
1) digital rectal examination (DRE)-most commonly done
2) PSA test
3) ultrasound
What does TNM classification of prostate cancer stand for
T = size and extend of tumour N = number of lymph nodes involved M= if it has metastasised
How many stages are in T and what are they
4 T1= small and localised tumour T2= palpable tumour T3= escape from prostate gland T4= local spread to pelvic region
numbering and meaning of N
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
numbering and meaning of M
M1a= Non-regional lymph nodes M1b= Bone M1c= Other sites
what are the 4 prostate cancer treatment
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
what is PTen
-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.
which gene fusion is frequent in prostate cancer
TMPRSS2-ERG fusion
Androgen Receptor (AR) signalling
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
how does the process go from cholesterol to cell growth
cholesterol - testosterone- DHT- AR binding -AR translocation- AR DNA binding - AR co-factor recruitment - AR transactivation- Cell growth
What is used to inhibit androgen synthesis
Abiraterone acetate (ZYTIGA)
what are the names of the super agonist and antagonist used to depress testosterone production in the testes
Goserelin- super agonist
Abarelix - Antagonist
what is used to inhibit the conversion from testosterone to DHT
5alpha-reductase inhibitors( finasteride and dutasteride)
what is used to prevent androgen binding to its receptor
competitive anti-androgen ( Bicalutamide, Enzalutamide, Flutamide, Nilutamide)
what are the 8 methods by which resistance can occur in prostate cancer treatment
- 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.
