19. hormone dependent cancer Flashcards
where is the prostate gland?
it is based at the bottom of the bladder and surrounds the urethra
what happens when their is overgrowth in the prostate?
the urethra is blocked
the prostate gland is a secretory gland, what does it secrete? and where are these produced?
> factors that can nourish the sperm
proteases that can digest the seminal clot
produces a large proportion of seminal fluid
- produced in ducts
what are the gland that produce milk called? and what are they surrounded by?
mammary glands empty into large ducts and milk exits out the nipple
>surrounded by stroma
what are prostate ducts surrounded by?
stroma - this contains lots of smooth muscle for ejaculation contraction forcing ejaculation of the urethra
describe a single gland
secretory epithelial cells are cuboidal in shape and come together to form specialised glands
>substances accumulate in the lumen and then are expelled
what type of glands are breast and prostate?
exocrine - secrete their products into ducts
what are the stroma that surround the prostate gland?
smooth muscle, fibroblasts, nerves and lymphatics
what is the function of the basal epithelial layer of cells?
ensure that secretions are forced out the duct - they high tight cell-cell junctions to prevent escape into serum
what are the secretory cells called in the prostate?
luminal epithelial cells
which cells are the major cell type in the prostate gland and how are they implicated in cancer?
luminal epithelial cells
these are the cells which cancer most commonly arises in
which cell type in the prostate are androgen dependent for growth?
luminal epithelial cells
are basal epithelial cells reliant on androgens for growth?
no
where is the stem cell population believed to be in the prostate?
basal epithelial cells
where do >90% breast and prostate cancers arise ?
in luminal epithelial cells
what happens to the basal epithelial layer of cells when cancer arises?
in all prostate cancer and most breast, this layer of cells disappears
what happens as tumour becomes more aggressive?
there is increasing loss of glandular structure
how common is breast and prostate cancer? and how well is it diagnosed?
very
>after skin cancer they are the most commonly diagnosed
what has the largest death rate?
lung cancer - it is not easily diagnosed
what is the lifetime risk of breast cancer
1 in 8
how many people develop and how many people die of breast cancer a year in the UK
50,000
12,000 - 2nd largest killer after lung
since introduction of mass breast screening what was seen?
reduction in mortality - early detection gives patient better prognosis
name 11 risk factors for breast cancer
- age
- race
- environment
- diet
- family size
- age of first pregnancy
- age of first period
- age of menopause
- exogenous hormones
- obesity
- family history
how is age implicated in breast cancer?
breast cancer is more common in the over 50s
how is race implicated in breast cancer?
higher incidence in the west
how is family size implicated in breast cancer?
changes in the mammary gland structure which are associated with pregnancy can also be protective
>having a baby before 30 seems to be protective
how is age of first pregnancy, period and menopause implicated in breast cancer?
fewer menstrual cycles in a lifetimes the lower the risk of breast cancer
how are oral contraceptive implicated in hormone dependent cancer?
reduce the risk of endometrium and ovarian cancer but do appear to slightly increase the risk of breast cancer
>this is reversible, stop taking the pill and risk decreases
how is weight implicated in breast cancer?
fat tissue can synthesise steroid hormones, obesity is associated with increased risk of breast cancer
how does the diet implicate breast cancer?
the vegetarian diet reduces the risk of breast cancer
how is family history implicated in breast cancer?
increases risk of breast cancer although most breast cancers are sporadic
>familial breast cancer is heterogeneous
name 4 genes implicated in familial breast cancer
BRCA1
BRCA2
PTEN
p53
what can be done for women worried they may get familial breast cancer?
> genetic screens
>removal of breast
how penetrant are BRCA mutations?
highly
>70% BRCA1 carriers with family history develop tumours by age 70
how much of breast cancer do familial BRCA1 and BRCA2 cases account for?
2-5%
what are BRCA1 and BRCA2?
TS involved in DNA damage and transcription
>BRCA1 is involved in non-homologous end joining
>BRCA2 is involved in nucleotide excision
what is the lifetime risk of prostate cancer?
1 in 8
how is the incidence of prostate cancer changing?
it is increasing (even after age adjustment)
name 4 risk factors in prostate cancer?
- age
- race
- family history
- diet
how is race implicated in prostate cancer
higher incidence in those of African descent - this may be due to genetic polymorphism
how is diet implicated in prostate cancer
- red meats, dairy and high fats
- protective effect of vegetarian diet and soya
prostate cancer in familial cases is very heterogeneous. name two genes which are implicated in familial prostate cancer
- PTEN
- BRCA2
how is PTEN implicated in prostate cancer?
mutations can cause prostate cancer progression in an aggressive manner
how us BRCA2 implicated in prostate cancer?
accounts for 5% of familial prostate cancers
>most highly linked tumour suppresser genes in prostate cancer
>highly penetrance, 5 fold higher lifetime risk, increases to 7 fold after 65
what are two symptoms are an enlarged prostate? and why this often lately diagnoses?
problems urinating
lower back pains
>can also be asymptomatic as very internalised gland
give 5 ways prostate cancer can be detected
- digital rectal examination
- PSA test
- ultrasound
- MRI
- biopsy
with a digital rectal exam, what should the prostate feel like?
- the size of a walnut
- smooth
what is PSA?
protease produced by prostate epithelia
how should PSA levels vary between semen and blood serum?
1 million times greater in semen than blood
what does high levels of PSA indicate?
disruption of the basal epithelia cells and basement membrane - could be due to cell invasion or mechanical disruption
what type of assay is the PSA test?
an antibody based assay - uses antibodies to show the presence of proteins
what 4 things may increased PSA levels in serum mean?
- cancer
- benign hyperplasia (might not lead to cancer)
- infection
- mechanical damage
why is PSA test not done routinely?
not specific enough
what is the threshold for the PSA test?
4ng/ml
what does the levels of PSA in the serum correlate with?
clinical staging of the disease
what is the PSA test useful to monitor?
how treatment is going
how many stages are there of prostate cancer? and what is this used for?
4
>to see how much the tumour has spread
define T1 of prostate cancer
cancer is small and localised
define T2 of prostate cancer
tumour becomes palpable
define T3 of prostate cancer
tumour escapes the prostate, it can now be viewed on an ultra sound
define T4 of prostate cancer
local spread to pelvic region
where does prostate cancer often metastasise to?
the bone, liver and kidneys
name another type of prostate cancer grading and describe it
Gleason grading
>grades cancer on the ability to form gland-like structures determined by biopsy
>by grade 5, tumour is sheets of de-differentiated cells
how does treatment of prostate cancer vary?
varies between stage of tumour and with age i.e. how it will affect the patient
what is done when the tumour is low grade and the patient is old?
active surveillance
>PSA to monitor tumour - if remains low grade will not be life threatening, if PSA increases further treatment may be needed
what is done if the tumour if confined to the prostate?
- radical prostatectomy - not very popular as can affect nerve endings (erectile dysfunctions and incontinence)
what is done if the prostate is locally spread?
radiotherapy
what is done if the prostate cancer has metastasised?
- hormone therapy
- chemotherapy
what are all steroid hormones made from?
synthesised from cholesterol obtained in the diet
name three steroid hormones
- androgens
- progesterone
- oestrogen
what happens if you affect one level of steroid hormone
various precursor stages are linked and so this will have a knock on effect on others
what can oestrogen be made out of?
testosterone
what is common about the structure of steroid hormones?
four ring structures
what property of steroid hormones means that they can cross cell membranes?
they are lipid soluble
what control the production of steroid hormones?
the hypothalamus and the pituitary gland
name 4 places steroid hormones can be synthesised
- testis
- ovaries
- thyroid
- adrenal
what does the adrenal gland produce precursors for?
androgens
what do steroid hormones do?
they circulate in the blood and act on target tissue
how are the levels of steroid hormones regulated?
> hypothalamus releases hormone that regulate pituitary gland
pituitary gland releases hormones that regulates steroid hormone producing glands
levels of steroid hormones negatively regulate both the hypothalamus and the pituitary gland
describe steroid hormone receptors
> member of nuclear receptor family
very similar in functional domain structure and aa seq
ligand dependent TF
DBD, ligand BD and TA domain
where do TF bind?
response element in promoter region
describe the DNA binding domains of steroid hormone receptors
two Zinc finger motifs
which domain of steroid hormone receptors is also involved in dimerization?
DNA binding domains and C terminal domain
describe the C terminus of steroid hormone receptors
binds ligand, involved in dimerization and binds heat shock proteins
which two regions of steroid hormone receptors are involved in TA?
AF-1 and AF-2 - the balance between the two is different between receptors
how do steroid hormone receptors bind DNA
as homodimers
describe the RE of oestrogen and androgen receptors
> oestrogen receptors has a specific response element
androgen receptor shares its response element with some other receptors
palindromic sequence (repeated on opposite strand in reverse) of 6 nucleotides separated by any 3 nucleotides
why is the spacing between the two palindromic sequences important?
so the two zinc fingers can each sit in the major groove
describe the LBD of the receptor
11 to 12 conserved alpha helices which form a ligand binding pocket
what happens when a ligand binds LBD of receptor
large displacement of helix 12 (the C terminal helix)
describe helix 12 in unbound and bound form
> in the absence of the ligand helix 12 is free to move around
when ligand binds, helix 12 forms ligand binding pocket, it makes a lid to hold the ligand in place
in addition to the formation of the ligand binding pocket, what else does the relocation of helix 12 do?
creates an important interaction surface to which coactivators and factors that promote transcriptions can bind
what sequence do coactivator which bind this interaction surface tend to have?
leucine rich motif
when testosterone is not present in the cytoplasm, what does AR bind and what does this do?
heat shock proteins
>these hold AR as a correctly folded protein, ready to bind androgens
when androgens enter the cell, what happens?
they are converted to dihydroxytestosterone by alpha reductase
>this is the most potent androgen
when androgen binds AR rector, what happens?
AR dimerises, this induces conformation changes which exposes the NLS
what does the a rearrange helix 12 form?
the co-activator binding surface - binds co-activators and drives prostate growth
define one co-activator
SCR1 - steroid receptor co-activator 1, this is part of the p160 family
>these are highly related and not specific
>they act on all nuclear receptors
what do co-activators do?
interacts with transcriptionally competent receptors in the presence of a ligand
>they do not bind DNA itself
- they increase the activity of the ligand bound receptor
what was used to show coactivator SCR1 increases ligand-dependent activity of AR ?
luciferase reporter assay
describe the receptor interaction LxxLL domain on SCR1
there are 3 in the receptor interaction domain
>there is another at the C term - this interact with the other end of the ligand activated receptor
>these motifs are short alpha helices
in terms of transcription, what does the co-activator do?
stabilises the formation of the RNA polymerase holoenzyme
describe nucleosomes
8 histones (2xH2A, 2xH2B, 2xH3 and 2xH4) >these wrap around each other to form a supercoil - DNA packing
what are steroid hormone receptors good at doing which lots of other TF are not very good at doing?
finding their response elements when the chromatin is more compact - they bind these and recruit factors to open up the chromatin
what do HAT coactivators form contact with?
receptors and basal transcription machinery
what do HDACs do?
reduce access for other transcription factors and polymerases
co-activators recruit proteins with HAT activity, what else can they do?
can act as scaffold to recruit larger complexes such as the TRAP/DRIP complex
what does TRAP/DRIP stand for?
thyroid receptor associated protein
vitamin D receptor interacting complex
what is the TRAP/DRIP complex?
>12 protein complex >recruited to activated receptors >essential for transcription >recruits RNAPII holoenzyme >acetylates histones and P CTD of RNAP to allow promoter clearance and progression
what is TRAP/DRIP related to?
the yeast mediator complex
name one nuclear receptor co-repressor
the NurD complex
what do co-repressor do?
promote gene silencing - chromatin compaction/prevent binding to DNA
what happens in terms of co-activators and co-repressors with thyroid receptors
> co-repressors bind to un-ligated receptors on response element (where it always binds)
when ligand binds receptor the co-repressor dissociates and co-activators bind to promote transcription
how might hormone antagonists used in treatment for breast and prostate cancer function? and what is exploited in therapy?
> promote interactions between receptor and co-repressors
co-repressors may be recruited to the antagonist bound receptor
=the fact that antagonists change the conformation of receptors and recruits co-represses
