Nuclear hormone receptors Flashcards
what are the largest family of TFs
steroid hormones
where is cortisol produced?
adrenal glands
what is cortisol
a cortisol steroid hormone
what needs to happen in order for cortisol to be released from the adrenal glands?
stress causes the hypothalamus to release corticotropin releasing factor which induces the pituitary to produce adrenocorticotropic hormone
this induces the adrenal Glands to secrete cortisol
what effect does cortisol have on cells
indues the expression of genes in target cells
where is the glucocorticoid receptor found?
in the cytoplasm and then translocates into cells
structure of glucocorticoid receptors in the absence of hormone?
complex with chaperones which iNHIBIT its activity
example of a chaperone which inhibits a gc receptors activity
heat shock protein 90
what happens to gc receptors when a ligands binds?
heat shock proteins dissociate
receptor translocates to the nucleus and binds to DNA named gc responsive elements
what does the gc bound gc receptor bind to in the nucleus
glucocorticoid responsive elements
where typically is the DNA which transcription factors induce in relation to where the TF binds?
usually the DNA sequences are found upstream of the where the TF bind
what does the effect which gcs have on cells depend on?
many factors
what effect do glucocorticoid receptors have on bcl-2 family?
induces the expression of this pro apoptotic family
Inhibits the expression of anti-apoptotic bcl-2 members such as MCL-1
examples of bcl-2 family members which gc can induce the expression of. effects what?
Bim and Noxa
PRO-APOPTOTIC
examples of bcl-2 family members which gcr’s can reduce the expression of? effect?
mcl-1
anti-apoptotic
what are estradiol and testosterone produced from?
cholesterol
in pre-menopausal women, oestrogen production is ______
cyclical
what controls the release of gonadotroipin releasing hormone?
the circadian rhythm
what does gonadotropin releasing hormone do?
reacts with the anterior pituitary leading to the release of LH and FSH
in post menopausal women the ______ ______ is the main site of oestrogen production
adipose tissue
what enzyme converts estrange to estradiol?
17 b hydroxyl dehydrogenase
what happens when oestrogen binds to its receptor?
actives the oestrogen receptor which then binds to specific DNA sites called oestrogen responsive elements
oestrogen molecules exert their effects where?
in tissues expressing oestrogen receptors
what effect does LH and FSH have on the ovaries?
produce oestrogen
what does SERMs stand for?
selective estrogen receptor modulators
___% of breast cancers in post menopausal women have hormone receptor positive disease
80
___% of breast cancers in pre menopausal women have hormone receptor positive disease
50
what is the degree of positivity defined by in oestrogen receptor positive breast cancers?
the level of expression of oestrogen and progesterone receptors
oestrogen effect on cells in the urterus and breast regarding proliferation?
promotes proliferation
what is chemical ablation when treating cancer in receptor positive cancers? administration?
reduce hormone synthesis via gonadotropin releasing hormone agonist e.g. gosereilin
monthly depot injection
what are the most common treatments in breast cancer? what do they do?
selective oestrogen receptor modulators (SERMs)
to block the action of oestrogen
example of a SERM
tamoxifen
TF: tamoxifen can be used in pre and post menopausal women
true
how does tamoxifen work
by binding to the oestrogen receptor
why doesn’t tamoxifen binding to the oestrogen receptor activate it
as it doesn’t cause the conformational change required
what effects can SERMs and oestrogen receptor ligand have in non target cells? where does this commonly occur and why?
act as oestrogen and cause activation of receptors
in the uterus it has mixed agonist/ antagonist effects
what must be monitor SERMs for? with which drug in particular?
uterine cancer
tamoxifen has been shown to act like oestrogen in the uterus
what has tamoxifen been replaced with and why?
raloxifene as it have anti-oestrogen activity in the breasts and no effect in the uterus
how can we reduce the levels of oestrogen in post menopausal women? (gold standard drugs)
aromatase inhibitors
what is aromatase
the enzyme which converts androgens to oestrogen’s
TF aromatase inhibitors are contraindicated in pre-menopausal women?
true unless ovarian suppression has been induced
what are the androgens
testosterone
androstenedione
what are the oestrogen’s
estradiol
estrone
in oestrogen receptor positive cancers what doe cells proliferate under the control od?
oesterogen
can tamoxifen treat oestrogen receptor negative cells
no as the cells aren’t governed by oestrogen so blocking these receptors will have no effect
gonadotropin releasing hormone is secreted in what fashion in men?
pulsatile
effect of gonadotropin releasing hormone release in men
pituitary to secrete LH and FSH
effect of LH in men?
stimulates leading cells of the testes to secrete testosterone
testosterone can now be converted into its active form DHT
what enzyme catalyses the conversion of testosterone to DHT (dihydrotestosterone)?
5-a reducase
how can DHT cause cell proliferation?
bind to androgen receptors which goes to DNA and causes proliferation
where does DHT binding to androgen receptors occur in cells
in the cytosol
what does the activated androgen receptor do (in men when DHT binds to it). what does this cause?
binds to androgen responsive elements in the nucleus and this causes production of prostate specific antigen
how is prostate specific antigen produced?
DHT binds to the androgen receptor which moves to the nucleus and induces genes for its expression
adrenal glands contribute to approximately ___% of the total circulating androgen pool in men
10
what is the main aim of hormonal therapy in prostate cancer?
interrupt the production of testosterone
4 approaches to interrupt testosterone production using hormonal therapy in prostate cancer
surgical removal of testes
suppress LH releasing hormone’s stimulation of the pituitatry using agonists to prevent LH release
inhibition of 5-a reductase to stop testosterone production in the prostate
blocking dihydrotestosterone to the androgen receptors in the prostate
what occurs in all prostate cancer patients after about 11 months
castration resistance prostate cancer
what is castration resistant prostate cancer?
when the patient no longer responds to androgen depletion therapy
mechanisms underlying castration resistant prostate cancer?
AR amplification
mutations
phosphorylation and methylation
androgen receptor active splice variants
what can be given in metastatic castration resistant prostate cancer?
next generation hormonal therapies:
CYP17A1 inhibitor (abiraterone)
or androgen receptor antagonist enzalutamine
abiraterone moa?
depletes androgen synthesis pathway precursors
TF there can also be resistance to abiraterone and enzalutamine
true
usually after 1-2 years
what is the main change associated with castration resistance and also resistance to abiraterone and enzalutamine
androgen receptor alterations
what is a hypothesis of why androgen receptors which are mutated can lead to disease progression and resistance
mutations cause the androgen receptors to be activated through other steroid ligands such as oestrogen, progesterone and glucocorticoids
what is the main change implicated in developing acquired resistance to abiraterone
androgen receptor splice variants
what is one of the most important hormone inhibition escape strategies adopted by prostate cancer cells?
splicing of the androgen receptor which results in the expression of different alternative androgen receptor variants
2 approaches which can be adopted to overcome alternative splicing
- adoping agents able to modulate androgen receptor variants transcription
- develop drugs targeting these specific variants
what drug can be a choice to overcome abiraterone?
enzalutamide
enzalutamide mechanisms of action?
inhibits androgen receptors by:
competing with DHT for binding
inhibiting nuclear translocation
blocking DNA
What is prostate specific antigen?
serum protease and a member of the human kallikrein family
what can prostate specific antigen be used to detect? how
prostate cancer
elevated in men with untreated prostate cancer- diagnostics
if levels of prostate specific antigens are >4ng/ml what does this suggest?
that the cancer has spread to the prostate capsule or beyond
NOT IN ALL MEN
what is the recommended amount of prostate specific antigen which many clinicians recommend a prostate biopsy?
> 2.5ng/ml
