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Cancer Biology and Therapy > Nuclear hormone receptors > Flashcards

Nuclear hormone receptors Flashcards

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1
Q

what are the largest family of TFs

A

steroid hormones

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2
Q

where is cortisol produced?

A

adrenal glands

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3
Q

what is cortisol

A

a cortisol steroid hormone

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4
Q

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

A

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

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5
Q

what effect does cortisol have on cells

A

indues the expression of genes in target cells

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6
Q

where is the glucocorticoid receptor found?

A

in the cytoplasm and then translocates into cells

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7
Q

structure of glucocorticoid receptors in the absence of hormone?

A

complex with chaperones which iNHIBIT its activity

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8
Q

example of a chaperone which inhibits a gc receptors activity

A

heat shock protein 90

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9
Q

what happens to gc receptors when a ligands binds?

A

heat shock proteins dissociate

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

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10
Q

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

A

glucocorticoid responsive elements

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11
Q

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

A

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

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12
Q

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

A

many factors

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13
Q

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

A

induces the expression of this pro apoptotic family

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

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14
Q

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

A

Bim and Noxa

PRO-APOPTOTIC

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15
Q

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

A

mcl-1

anti-apoptotic

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16
Q

what are estradiol and testosterone produced from?

A

cholesterol

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17
Q

in pre-menopausal women, oestrogen production is ______

A

cyclical

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18
Q

what controls the release of gonadotroipin releasing hormone?

A

the circadian rhythm

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19
Q

what does gonadotropin releasing hormone do?

A

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

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20
Q

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

A

adipose tissue

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21
Q

what enzyme converts estrange to estradiol?

A

17 b hydroxyl dehydrogenase

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22
Q

what happens when oestrogen binds to its receptor?

A

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

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23
Q

oestrogen molecules exert their effects where?

A

in tissues expressing oestrogen receptors

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24
Q

what effect does LH and FSH have on the ovaries?

A

produce oestrogen

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25
Q

what does SERMs stand for?

A

selective estrogen receptor modulators

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26
Q

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

A

80

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27
Q

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

A

50

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28
Q

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

A

the level of expression of oestrogen and progesterone receptors

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29
Q

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

A

promotes proliferation

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30
Q

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

A

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

31
Q

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

A

selective oestrogen receptor modulators (SERMs)

to block the action of oestrogen

32
Q

example of a SERM

A

tamoxifen

33
Q

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

A

true

34
Q

how does tamoxifen work

A

by binding to the oestrogen receptor

35
Q

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

A

as it doesn’t cause the conformational change required

36
Q

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

A

act as oestrogen and cause activation of receptors

in the uterus it has mixed agonist/ antagonist effects

37
Q

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

A

uterine cancer

tamoxifen has been shown to act like oestrogen in the uterus

38
Q

what has tamoxifen been replaced with and why?

A

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

39
Q

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

A

aromatase inhibitors

40
Q

what is aromatase

A

the enzyme which converts androgens to oestrogen’s

41
Q

TF aromatase inhibitors are contraindicated in pre-menopausal women?

A

true unless ovarian suppression has been induced

42
Q

what are the androgens

A

testosterone

androstenedione

43
Q

what are the oestrogen’s

A

estradiol

estrone

44
Q

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

A

oesterogen

45
Q

can tamoxifen treat oestrogen receptor negative cells

A

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

46
Q

gonadotropin releasing hormone is secreted in what fashion in men?

A

pulsatile

47
Q

effect of gonadotropin releasing hormone release in men

A

pituitary to secrete LH and FSH

48
Q

effect of LH in men?

A

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

49
Q

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

A

5-a reducase

50
Q

how can DHT cause cell proliferation?

A

bind to androgen receptors which goes to DNA and causes proliferation

51
Q

where does DHT binding to androgen receptors occur in cells

A

in the cytosol

52
Q

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

A

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

53
Q

how is prostate specific antigen produced?

A

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

54
Q

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

A

10

55
Q

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

A

interrupt the production of testosterone

56
Q

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

A

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

57
Q

what occurs in all prostate cancer patients after about 11 months

A

castration resistance prostate cancer

58
Q

what is castration resistant prostate cancer?

A

when the patient no longer responds to androgen depletion therapy

59
Q

mechanisms underlying castration resistant prostate cancer?

A

AR amplification
mutations
phosphorylation and methylation
androgen receptor active splice variants

60
Q

what can be given in metastatic castration resistant prostate cancer?

A

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

61
Q

abiraterone moa?

A

depletes androgen synthesis pathway precursors

62
Q

TF there can also be resistance to abiraterone and enzalutamine

A

true

usually after 1-2 years

63
Q

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

A

androgen receptor alterations

64
Q

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

A

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

65
Q

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

A

androgen receptor splice variants

66
Q

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

A

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

67
Q

2 approaches which can be adopted to overcome alternative splicing

A
  1. adoping agents able to modulate androgen receptor variants transcription
  2. develop drugs targeting these specific variants
68
Q

what drug can be a choice to overcome abiraterone?

A

enzalutamide

69
Q

enzalutamide mechanisms of action?

A

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

70
Q

What is prostate specific antigen?

A

serum protease and a member of the human kallikrein family

71
Q

what can prostate specific antigen be used to detect? how

A

prostate cancer

elevated in men with untreated prostate cancer- diagnostics

72
Q

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

A

that the cancer has spread to the prostate capsule or beyond

NOT IN ALL MEN

73
Q

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

A

> 2.5ng/ml

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