Nuclear hormone receptors

Question 1

what are the largest family of TFs

Answer 1

steroid hormones

Question 2

where is cortisol produced?

Answer 2

adrenal glands

Question 3

what is cortisol

Answer 3

a cortisol steroid hormone

Question 4

what needs to happen in order for cortisol to be released from the adrenal glands?

Answer 4

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

Question 5

what effect does cortisol have on cells

Answer 5

indues the expression of genes in target cells

Question 6

where is the glucocorticoid receptor found?

Answer 6

in the cytoplasm and then translocates into cells

Question 7

structure of glucocorticoid receptors in the absence of hormone?

Answer 7

complex with chaperones which iNHIBIT its activity

Question 8

example of a chaperone which inhibits a gc receptors activity

Answer 8

heat shock protein 90

Question 9

what happens to gc receptors when a ligands binds?

Answer 9

heat shock proteins dissociate

receptor translocates to the nucleus and binds to DNA named gc responsive elements

Question 10

what does the gc bound gc receptor bind to in the nucleus

Answer 10

glucocorticoid responsive elements

Question 11

where typically is the DNA which transcription factors induce in relation to where the TF binds?

Answer 11

usually the DNA sequences are found upstream of the where the TF bind

Question 12

what does the effect which gcs have on cells depend on?

Answer 12

many factors

Question 13

what effect do glucocorticoid receptors have on bcl-2 family?

Answer 13

induces the expression of this pro apoptotic family

Inhibits the expression of anti-apoptotic bcl-2 members such as MCL-1

Question 14

examples of bcl-2 family members which gc can induce the expression of. effects what?

Answer 14

Bim and Noxa

PRO-APOPTOTIC

Question 15

examples of bcl-2 family members which gcr’s can reduce the expression of? effect?

Answer 15

mcl-1

anti-apoptotic

Question 16

what are estradiol and testosterone produced from?

Answer 16

cholesterol

Question 17

in pre-menopausal women, oestrogen production is ______

Answer 17

cyclical

Question 18

what controls the release of gonadotroipin releasing hormone?

Answer 18

the circadian rhythm

Question 19

what does gonadotropin releasing hormone do?

Answer 19

reacts with the anterior pituitary leading to the release of LH and FSH

Question 20

in post menopausal women the ______ ______ is the main site of oestrogen production

Answer 20

adipose tissue

Question 21

what enzyme converts estrange to estradiol?

Answer 21

17 b hydroxyl dehydrogenase

Question 22

what happens when oestrogen binds to its receptor?

Answer 22

actives the oestrogen receptor which then binds to specific DNA sites called oestrogen responsive elements

Question 23

oestrogen molecules exert their effects where?

Answer 23

in tissues expressing oestrogen receptors

Question 24

what effect does LH and FSH have on the ovaries?

Answer 24

produce oestrogen

Question 25

what does SERMs stand for?

Answer 25

selective estrogen receptor modulators

Question 26

___% of breast cancers in post menopausal women have hormone receptor positive disease

Answer 26

80

Question 27

___% of breast cancers in pre menopausal women have hormone receptor positive disease

Answer 27

50

Question 28

what is the degree of positivity defined by in oestrogen receptor positive breast cancers?

Answer 28

the level of expression of oestrogen and progesterone receptors

Question 29

oestrogen effect on cells in the urterus and breast regarding proliferation?

Answer 29

promotes proliferation

Question 30

what is chemical ablation when treating cancer in receptor positive cancers? administration?

Answer 30

reduce hormone synthesis via gonadotropin releasing hormone agonist e.g. gosereilin monthly depot injection

Question 31

what are the most common treatments in breast cancer? what do they do?

Answer 31

selective oestrogen receptor modulators (SERMs) | to block the action of oestrogen

Question 32

example of a SERM

Answer 32

tamoxifen

Question 33

TF: tamoxifen can be used in pre and post menopausal women

Answer 33

true

Question 34

how does tamoxifen work

Answer 34

by binding to the oestrogen receptor

Question 35

why doesn't tamoxifen binding to the oestrogen receptor activate it

Answer 35

as it doesn't cause the conformational change required

Question 36

what effects can SERMs and oestrogen receptor ligand have in non target cells? where does this commonly occur and why?

Answer 36

act as oestrogen and cause activation of receptors | in the uterus it has mixed agonist/ antagonist effects

Question 37

what must be monitor SERMs for? with which drug in particular?

Answer 37

uterine cancer | tamoxifen has been shown to act like oestrogen in the uterus

Question 38

what has tamoxifen been replaced with and why?

Answer 38

raloxifene as it have anti-oestrogen activity in the breasts and no effect in the uterus

Question 39

how can we reduce the levels of oestrogen in post menopausal women? (gold standard drugs)

Answer 39

aromatase inhibitors

Question 40

what is aromatase

Answer 40

the enzyme which converts androgens to oestrogen's

Question 41

TF aromatase inhibitors are contraindicated in pre-menopausal women?

Answer 41

true unless ovarian suppression has been induced

Question 42

what are the androgens

Answer 42

testosterone | androstenedione

Question 43

what are the oestrogen's

Answer 43

estradiol | estrone

Question 44

in oestrogen receptor positive cancers what doe cells proliferate under the control od?

Answer 44

oesterogen

Question 45

can tamoxifen treat oestrogen receptor negative cells

Answer 45

no as the cells aren't governed by oestrogen so blocking these receptors will have no effect

Question 46

gonadotropin releasing hormone is secreted in what fashion in men?

Answer 46

pulsatile

Question 47

effect of gonadotropin releasing hormone release in men

Answer 47

pituitary to secrete LH and FSH

Question 48

effect of LH in men?

Answer 48

stimulates leading cells of the testes to secrete testosterone testosterone can now be converted into its active form DHT

Question 49

what enzyme catalyses the conversion of testosterone to DHT (dihydrotestosterone)?

Answer 49

5-a reducase

Question 50

how can DHT cause cell proliferation?

Answer 50

bind to androgen receptors which goes to DNA and causes proliferation

Question 51

where does DHT binding to androgen receptors occur in cells

Answer 51

in the cytosol

Question 52

what does the activated androgen receptor do (in men when DHT binds to it). what does this cause?

Answer 52

binds to androgen responsive elements in the nucleus and this causes production of prostate specific antigen

Question 53

how is prostate specific antigen produced?

Answer 53

DHT binds to the androgen receptor which moves to the nucleus and induces genes for its expression

Question 54

adrenal glands contribute to approximately ___% of the total circulating androgen pool in men

Answer 54

10

Question 55

what is the main aim of hormonal therapy in prostate cancer?

Answer 55

interrupt the production of testosterone

Question 56

4 approaches to interrupt testosterone production using hormonal therapy in prostate cancer

Answer 56

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

Question 57

what occurs in all prostate cancer patients after about 11 months

Answer 57

castration resistance prostate cancer

Question 58

what is castration resistant prostate cancer?

Answer 58

when the patient no longer responds to androgen depletion therapy

Question 59

mechanisms underlying castration resistant prostate cancer?

Answer 59

AR amplification mutations phosphorylation and methylation androgen receptor active splice variants

Question 60

what can be given in metastatic castration resistant prostate cancer?

Answer 60

next generation hormonal therapies: CYP17A1 inhibitor (abiraterone) or androgen receptor antagonist enzalutamine

Question 61

abiraterone moa?

Answer 61

depletes androgen synthesis pathway precursors

Question 62

TF there can also be resistance to abiraterone and enzalutamine

Answer 62

true | usually after 1-2 years

Question 63

what is the main change associated with castration resistance and also resistance to abiraterone and enzalutamine

Answer 63

androgen receptor alterations

Question 64

what is a hypothesis of why androgen receptors which are mutated can lead to disease progression and resistance

Answer 64

mutations cause the androgen receptors to be activated through other steroid ligands such as oestrogen, progesterone and glucocorticoids

Question 65

what is the main change implicated in developing acquired resistance to abiraterone

Answer 65

androgen receptor splice variants

Question 66

what is one of the most important hormone inhibition escape strategies adopted by prostate cancer cells?

Answer 66

splicing of the androgen receptor which results in the expression of different alternative androgen receptor variants

Question 67

2 approaches which can be adopted to overcome alternative splicing

Answer 67

1. adoping agents able to modulate androgen receptor variants transcription 2. develop drugs targeting these specific variants

Question 68

what drug can be a choice to overcome abiraterone?

Answer 68

enzalutamide

Question 69

enzalutamide mechanisms of action?

Answer 69

inhibits androgen receptors by: competing with DHT for binding inhibiting nuclear translocation blocking DNA

Question 70

What is prostate specific antigen?

Answer 70

serum protease and a member of the human kallikrein family

Question 71

what can prostate specific antigen be used to detect? how

Answer 71

prostate cancer | elevated in men with untreated prostate cancer- diagnostics

Question 72

if levels of prostate specific antigens are >4ng/ml what does this suggest?

Answer 72

that the cancer has spread to the prostate capsule or beyond NOT IN ALL MEN

Question 73

what is the recommended amount of prostate specific antigen which many clinicians recommend a prostate biopsy?

Answer 73

>2.5ng/ml