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Mechanisms of disease > Intro to hormone dependent cancers > Flashcards

Intro to hormone dependent cancers Flashcards

1
Q

what is a hormone

A

chemical messenger made by specialist cells, usually within an endocrine gland and released into bloodstream to have effect in another part of the body

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2
Q

where are the hormones produced

A 
pineal gland 
hypothalamus 
pituitary 
thyroid 
thymus 
pancreas

adrenal cortex, kidneys

ovaries/uterus
testes

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3
Q

what 3 groups can hormones be put into

A

steroids = lipid soluble small molecules

peptide/proteins

modified amino acids/amine hormones

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4
Q

describe steroid hormones

A

all steroid hormones are synthesised from cholesterol

e.g:
androgen, estrogen, progesterone, corticosteroid, mineralocorticoid

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5
Q

describe sex hormones

A

responsible for sexual dimorphism between males and females

development of secondary sexual characteristics

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6
Q

describe steroid hormones 2

A

work systemically, have effects on several tissues

effects are:

females = oestrogen controls menstrual cycle and breast tissue development, fertility, reproductive organ development, secondary sexual characteristics, body hair etc

males = testosterone controls reproductive and supportive organs, development of sexual characteristics in men

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7
Q

list 5 top cancers in UK 2017

A 
breast
prostate
lung
bowel 
melanoma
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8
Q

briefly describe prostate and breast cancer

A

most common cancers in men and women

breast and prostate are tissues which are strongly controlled or influenced by steroid hormones

tissues are hormone dependent, as steroids govern their growth and development

steroids control several aspects of cellular proliferation, tissue function, gene expression and morphology of these tissues

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9
Q

hormones and cancer

A

when cancer arise in breast or prostate, steroid hormones can influence how cells grow and function and how disease develops

dependence of these tissues on steroids can be exploited when it comes to treatment of these cancers

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10
Q

describe steroid hormone action

A

once steroids enter cells, bind to receptors

receptors = nuclear receptors. have effects on nucleus, may be found in cytoplasm or nucleus initially

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11
Q

receptor mechanism described

A
  1. steroid hormones cross into cell cytoplasm where they bind to receptor
  2. binding to receptor = conformational change in nuclear receptor = activated
  3. nuclear receptors then translocate into nucleus
  4. nuclear receptors bind to specific DNA sequences = response elements, located in promoters of steroid responsive genes
  5. steroid responsive genes switched on and unregulated
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12
Q

describe key characteristics of nuclear receptors

A

LBD = ligand binding domain = binds specific steroid molecules with high affinity

DNA binding domain = binds specific DNA sequences

activation function domain = recruits gene activation machinery, some receptors have secondary AF2 domain towards C-terminal

same basic domains and structure shared with many major nuclear receptors

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13
Q

key characteristics of nuclear receptors p2

A

ligand activated receptors = when receptors bind steroid hormones they are activated

binding of steroids to ligand binding domain causes physical restricting of polypeptide chains in receptor, activating it

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14
Q

describe ligand activated transcription factors

A
  1. ligand binding to the ligand binding site = shift in alpha helix= activates receptor
  2. receptor dimerises, moves to nucleus and binds to specific DNA sequences
  3. receptor recruits DNA modifying enzymes
    e. g. histone deacetylases, other TFs
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15
Q

describe the DNA binding domain

A

contains 2 zinc finger domains = essential for sequence specific DNA binding

cl zinc finger = specific DNA sequence binding

cll zinc finger = interaction with the DNA phosphate backbone

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16
Q

describe hormone responsive genes

A

many hundreds of genes may be upregulated by steroid hormone receptor

some genes may be down regulated

genes include functional tissue specific genes, cell cycle and proliferation genes

genes involved in tissue development and differentiation

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17
Q

describe DNA binding and gene activation

A

hormone response elements = specific DNA sequences found in promoters of hormone responsive genes.

many are palindromic

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18
Q

nuclear receptor super-family

A

48 nuclear receptor genes in humans

all share common domain structure and are thought to arise from common evolutionary ancestor

share a structure that is activated by ligand binding

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19
Q

describe similarity of steroid receptors

A

receptors have high homology in DNA binding domain and differ in ligand binding domains, differ significantly in N terminal activation domains

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20
Q

list the main steroid receptors

A
  1. estrogen receptors = estradiol, estrone, estriol
  2. androgen receptor = androstenedione, testosterone, dihydrotestosterone
  3. progesterone receptor = progesterone, pregenolone
  4. glucocorticoid receptor = cortisol and cortisone
  5. mineralocorticoid receptor = aldosterone
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21
Q

the breast described

A

breast is an apocrine gland that produces milk
breast is composed of glands and ducts which produce fatty breast milk

milk producing part of breast is organised into 15-20 sections = lobes

within each lobe = smaller structures = lobules = where milk is produced

milk travels through network of tiny tubules called dicts = ducts connect and come together into larger ducts, eventually exit skin in nipple

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22
Q

describe apocrine gland

A

mammary gland is specialised type of exocrine gland called APOCRINE gland

exocrine gland = secrete substances out onto surface or cavity
endocrine gland = secrete substance directly into bloodstream

apocrine gland = specialised exocrine gland in which a part of cells cytoplasm breaks off releasing the contents

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23
Q

describe mammary gland tissue structure

A

two cell compartments:

luminal = form single layer of polarised epithelium around ductal lumen, luminal cells produce milk during lactation

basal = comprise of cells that do not touch lumen, basally oriented myoepithelial cells in contact with basement membrane, have contractile function during lactation

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24
Q

describe ER function in normal breast

A

two major phases distinguished in mammary gland development:

  • hormone independent from embryonic development up to puberty
  • hormone dependent thereafter during puberty, menstrual cycle and pregnancy
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25
Q

ER function in normal breast 2

A

estrogen = drives expression of genes involved in cellular proliferation and differentiation

hormone dependent mammary gland development occurs after puberty and results in ductal elongation and triggers side branching

in adult estrogen allows for ,maintenance of mammary gland tissue, primes tissue for effects of progesterone during pregnancy for milk production

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26
Q

progesterone activity in normal breast

A

estrogen mainly involved initial growth of breast cancer

progesterone receptor gene switched on by oestrogen receptor

progesterone increases branching of ducts

prolonged progesterone receptor activity i.e. during pregnancy leads to more side branching and lactogenic differentiation

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27
Q

describe breast cancer

A

occurs when abnormal cells in breast begin to grow and divide in uncontrolled way and form tumour

breast cancer starts in breast tissue, most commonly in cells that line milk ducts of breast

1 in 8 women may develop cancer in their lifetime

main risks are = age, lifestyle and genetic familial factors

28
Q

aetiology of breast cancer

A

age = increases with age, diagnosed after 50

genetic mutations to certain genes = BRCA1 and 2.

reproductive history = early onset of menstrual cycle before 12 years and starting menopause after 55yrs expose women longer to hormones

previous treatment using radiation therapy to chest or breasts = before age 30 have higher risk of getting breast cancer later in life

29
Q

aetiology of breast cancer 2

A

not being physically active

overweight or obese

taking hormones. hormone replacement during menopause can increase risk for breast cancer if taken for more 5 years

certain oral contraceptives found to increase risk too

reproductive history = first pregnancy after 30, not breastfeeding, never having full term pregnancy can all raise breast cancer risk

drinking alcohol = risk increases

30
Q

describe ductal breast carcinoma in situ (DCIS)

A

breast made up of lobules and ducts which are surrounded by glandular, fibrous and fatty tissue

when cancer cells develop within ducts of breast but remain within ducts = DCIS
cancer cells have yet to develop ability to spread outside these ducts into surrounding breast tissue or other parts of body

31
Q

describe lobular breast carcinoma in situ (LCIS)

A

uncommon condition which abnormal cells form in milk glands in breast

LCIS = not cancer
indicates increased risk of developing breast cancer

32
Q

describe ER expression in breast cancer

A

majority of breast cancers are ER positive and have good prognosis

remainder and ER negative and have poor prognosis

positive prognosis cannot be treated hormonally and patients are given conventional therapies

33
Q

describe breast cancer subtypes

A

oversimplification to classify breast cancer as positive or negative ER

several classifications of breast cancer

progesterone receptor is an indicator of estrogen activity but progesterone becoming more interesting target for cancer therapy as in some subtype it may reduce cell growth

34
Q

describe ER in breast cancer

A

signalling pathway is subverted and becomes uncontrolled

ERs ability to bind DNA and open chromatin becomes hijacked and used to transcribe genes, non coding RNAs and miRNAs

ER governs cancer cell proliferation and controls and influences many hundred of genes involved in metastasis, invasion and adhesion

35
Q

targeting ER in breast cancer

A

mammary gland is estrogen sensitive and dependent tissue

breast cancer cells retain sensitivity and dependency - estrogens key driver of breast cancer growth

used as inherent vulnerability that can be exploited for treatment

switch of ER signalling, switch off cancer growth

36
Q

describe inhibiting ER signalling

A

biopsy samples often analysed for ER expression. 75% of all breast cancers = ER positive

37
Q

describe inhibiting estrogen action

A

pharmaceutically competitively blocking estrogen binding to receptor and degrading ER protein

no ER signalling = no breast cancer cell growth

38
Q

fulvestrant (faslodex)

A
  • an analogue of estradiol
  • fulvestrant competitively inhibits binding of estradiol to ER with binding affinity that is 89% that of estradiol

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 AF1 and AF2 are disabled.
The fulvestrant–ER complex is unstable, resulting in accelerated degradation of the ER protein.

39
Q

tamoxifen

A
  • binds the ER at ligand binding site
  • partial agonist but does not cause full activation of ER
  • has mixed activity = activates ER in uterus and liver, but acts as antagonist in breast tissue

tamoxifen = selective estrogen receptor modulator

  • tamoxifen bound ER doesn’t fold properly and the AF2 domains do not function
40
Q

tamoxifen bound ER

A

estradiol binds deep within pocket in receptor and covered by loop of protein chain

loop forms part of activation signal = stimulates growth in cell

tamoxifen binds, extra tail of drug is too bulky and receptor loop not able to adopt its active conformation

41
Q

aromatase inhibitors

A

when ovaries aren’t functional in postmenopausal women, potential sources of estrogen come from peripheral conversion of androgen by aromatase enzyme

enzyme present in multiple organs, incl adipsose tissue, brain, blood vessels, skin, bone, endometrium and breast tissue

androgen are hormones such as testosterone or adrenal androgen such as androstenedione

42
Q

describe 2 types of aromatase inhibitors

A

type 1 = androgen analogues and bind irreversibly to aromatase, aka suicide inhibitors. duration of inhibitory effect = primarily dependent on rate of de novo synthesis of aromatase

type 2 inhibitors = contain functional group within ring structure that binds heme iron of cytochrome P450, interfering with hydroxylation reactions

43
Q

what’s the main function of prostate gland tissue

A

to produce prostatic fluid that creates semen when mixed with the sperm produced by the testes

44
Q

describe development of normal prostate

A

prostate gland development can be separated:

  • hormone independent from embryonic development up to puberty
  • enlargement during puberty
  • hormone dependent maintenance thereafter in adulthood
  • reactivation of prostate growth in old age, leading to hyperplasia and prostate cancer
45
Q

development of prostate abnormalities

A

inflammation: prostatitis = linked to infertility

dysregulated growth of prostate = benign and malignant

46
Q

symptoms of prostate cancer

A 
frequent trips to urinate
poor urinary stream 
urgent need to urinate 
hesitancy whilst urinating 
lower back pain 
blood in urine - rare
47
Q

describe methods to detect prostate cancer

A

digital rectal examination

PSA test

ultrasound to detect tumour

48
Q

prostate cancer grading

A

Gleason grading system = helps evaluate prognosis of men using prostate biopsy samples

samples examine by clinical histologist

prostate cancer stagin predicts prognosis and helps guide therapy

cancers with higher Gleason score = more aggressive and worse prognosis

49
Q

prostate cancer treatments

A

watchful waiting = low grade tumour, older patients

radical prostatectomy = stage T1 or T2

radical radiotherapy = external up to T3. internal implants for T1/2

hormone therapy = prostatectomy or radical radiotherapy. metastatic prostate cancer

50
Q

risk factors for prostate cancer

A
  • age = rare in younger men than 40.
  • race/ethnicity = more in African-american men and Caribbean men
  • geography = North America, north-western Europe and Australia and Caribbean islands most common
  • family history
  • gene changes/inherited = inherited BRCA1 or BRCA2 gene, men with Lynch syndrome caused by inherited gene changes
  • diet, obesity, chemical exposures, inflammation of prostate, sexually transmitted infections
51
Q

describe Pten

A

a phosphatase that antagonises phosphatidylinositol 3-kinase signalling pathway

PTEN is only know 3’ phsppahtase counteracting the PI3K/AKT pathway

loss of Pten results in increased growth factor signalling

52
Q

hormones and prostate

A

growth and development of prostate gland is dependent upon presence of androgens

most common androgen = testosterone, steroid hormone

testosterone produced in testes

53
Q

androgen recepto signalling

A

AR located in cytoplasm associated with many chaperone proteins

testosterone converted to a more potent agonist as it crossed into prostate

dihydrotestosterone then binds the AR

54
Q

targeting AR in prostate cancer

A

prostate gland is androgen sensitive and dependent tissue

prostate cancer cells retain sensitivity and dependency

androgens key driver of prostate cancer growth

this can be used as inherent vulnerability that can be exploited for treatment

switch off AR signalling = switch off cancer growth

AR targeting is the Achilles heel of prostate cancer

55
Q

inhibition of testosterone synthesis

A

adrenal gland derived androgens circulate in blood and finally converted to testosterone in testesd

testosterone circulates in blood where it reaches end target organs

adrenal androgen production can be inhibited, thus depriving testes of testosterone precursors.

56
Q

describe control of hormone production

A

GnRH

goserelin = super agonist

abarelix = antagonist

overall actions of superagonist and antagonist are similar, depress testosterone production in the testes

57
Q

describe inhibition of testosterone conversion to DHT

A

testosterone is converted in the prostate to a more potent androgen = dihydrotestosterone = drives prostate growth and function

58
Q

describe hormone therapies for cancer

A

work very well for breast and prostate cancer

overtime these therapies begin to fail and patients relapse with hormone refractory cancers

homogenous cancer cells develop various mechanisms to overcome hormonal starvation

59
Q

describe ligand binding site mutations

A

allow other hormones to bind

ligand binding site mutations make the receptors promiscuous

60
Q

describe receptor amplification

A

signal amplification and increased sensitivity to low hormone levels

61
Q

receptor phosphorylation/activation in the absence of ligand

A

cross over with other signal pathways

e.g. growth factors can phosphorylate and activate receptors

prevalent for breast cancers

62
Q

describe androgen receptor transcript variants: absence in the absence of ligand

A

AR = variant 7

truncated AR without C terminus

active without ligand in prostate cancer

63
Q

describe receptor bypass

A

possible switch to other transcription factors or oncogenes

64
Q

describe receptor cofactor amplification

A

cofactor amplification can amplify the signal from steroid receptors in response to low level of steroid hormones

65
Q

antagonists become agonists via LBD mutations

A

antagonist used for prostate cancer treatment can become potent activators of a mutant androgen receptor

Mechanisms of disease (29 decks)

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