Intro to hormone dependent cancers Flashcards
what is a hormone
chemical messenger made by specialist cells, usually within an endocrine gland and released into bloodstream to have effect in another part of the body
where are the hormones produced
pineal gland hypothalamus pituitary thyroid thymus pancreas
adrenal cortex, kidneys
ovaries/uterus
testes
what 3 groups can hormones be put into
steroids = lipid soluble small molecules
peptide/proteins
modified amino acids/amine hormones
describe steroid hormones
all steroid hormones are synthesised from cholesterol
e.g:
androgen, estrogen, progesterone, corticosteroid, mineralocorticoid
describe sex hormones
responsible for sexual dimorphism between males and females
development of secondary sexual characteristics
describe steroid hormones 2
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
list 5 top cancers in UK 2017
breast prostate lung bowel melanoma
briefly describe prostate and breast cancer
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
hormones and cancer
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
describe steroid hormone action
once steroids enter cells, bind to receptors
receptors = nuclear receptors. have effects on nucleus, may be found in cytoplasm or nucleus initially
receptor mechanism described
- steroid hormones cross into cell cytoplasm where they bind to receptor
- binding to receptor = conformational change in nuclear receptor = activated
- nuclear receptors then translocate into nucleus
- nuclear receptors bind to specific DNA sequences = response elements, located in promoters of steroid responsive genes
- steroid responsive genes switched on and unregulated
describe key characteristics of nuclear receptors
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
key characteristics of nuclear receptors p2
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
describe ligand activated transcription factors
- ligand binding to the ligand binding site = shift in alpha helix= activates receptor
- receptor dimerises, moves to nucleus and binds to specific DNA sequences
- receptor recruits DNA modifying enzymes
e. g. histone deacetylases, other TFs
describe the DNA binding domain
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
describe hormone responsive genes
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
describe DNA binding and gene activation
hormone response elements = specific DNA sequences found in promoters of hormone responsive genes.
many are palindromic
nuclear receptor super-family
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
describe similarity of steroid receptors
receptors have high homology in DNA binding domain and differ in ligand binding domains, differ significantly in N terminal activation domains
list the main steroid receptors
- estrogen receptors = estradiol, estrone, estriol
- androgen receptor = androstenedione, testosterone, dihydrotestosterone
- progesterone receptor = progesterone, pregenolone
- glucocorticoid receptor = cortisol and cortisone
- mineralocorticoid receptor = aldosterone
the breast described
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
describe apocrine gland
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
describe mammary gland tissue structure
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
describe ER function in normal breast
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
ER function in normal breast 2
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
progesterone activity in normal breast
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
describe breast cancer
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
aetiology of breast cancer
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
aetiology of breast cancer 2
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
describe ductal breast carcinoma in situ (DCIS)
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
describe lobular breast carcinoma in situ (LCIS)
uncommon condition which abnormal cells form in milk glands in breast
LCIS = not cancer
indicates increased risk of developing breast cancer
describe ER expression in breast cancer
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
describe breast cancer subtypes
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
describe ER in breast cancer
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
targeting ER in breast cancer
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
describe inhibiting ER signalling
biopsy samples often analysed for ER expression. 75% of all breast cancers = ER positive
describe inhibiting estrogen action
pharmaceutically competitively blocking estrogen binding to receptor and degrading ER protein
no ER signalling = no breast cancer cell growth
fulvestrant (faslodex)
- 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.
tamoxifen
- 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
tamoxifen bound ER
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
aromatase inhibitors
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
describe 2 types of aromatase inhibitors
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
what’s the main function of prostate gland tissue
to produce prostatic fluid that creates semen when mixed with the sperm produced by the testes
describe development of normal prostate
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
development of prostate abnormalities
inflammation: prostatitis = linked to infertility
dysregulated growth of prostate = benign and malignant
symptoms of prostate cancer
frequent trips to urinate poor urinary stream urgent need to urinate hesitancy whilst urinating lower back pain blood in urine - rare
describe methods to detect prostate cancer
digital rectal examination
PSA test
ultrasound to detect tumour
prostate cancer grading
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
prostate cancer treatments
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
risk factors for prostate cancer
- 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
describe Pten
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
hormones and prostate
growth and development of prostate gland is dependent upon presence of androgens
most common androgen = testosterone, steroid hormone
testosterone produced in testes
androgen recepto signalling
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
targeting AR in prostate cancer
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
inhibition of testosterone synthesis
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.
describe control of hormone production
GnRH
goserelin = super agonist
abarelix = antagonist
overall actions of superagonist and antagonist are similar, depress testosterone production in the testes
describe inhibition of testosterone conversion to DHT
testosterone is converted in the prostate to a more potent androgen = dihydrotestosterone = drives prostate growth and function
describe hormone therapies for cancer
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
describe ligand binding site mutations
allow other hormones to bind
ligand binding site mutations make the receptors promiscuous
describe receptor amplification
signal amplification and increased sensitivity to low hormone levels
receptor phosphorylation/activation in the absence of ligand
cross over with other signal pathways
e.g. growth factors can phosphorylate and activate receptors
prevalent for breast cancers
describe androgen receptor transcript variants: absence in the absence of ligand
AR = variant 7
truncated AR without C terminus
active without ligand in prostate cancer
describe receptor bypass
possible switch to other transcription factors or oncogenes
describe receptor cofactor amplification
cofactor amplification can amplify the signal from steroid receptors in response to low level of steroid hormones
antagonists become agonists via LBD mutations
antagonist used for prostate cancer treatment can become potent activators of a mutant androgen receptor
