Hormone-Dependent Cancers Flashcards
Describe the characteristics of a steroid hormone.
Steroids – lipid soluble small molecules
All steroid hormones are synthesised from
cholesterol
> Recall 4 ring structure which is the ‘backbone’ of steroid hormones
Understand the sources and tissues that produce hormones and identify those tissues that respond to hormones
in females oestrogen controls:
the menstrual cycle
breast tissue development
fertility, and reproductive organ development
secondary sexual characteristics - body hair etc.
in males testosterone controls:
reproductive and supportive organs (prostate)
development of sexual characteristics in men
e.g. deepening of the voice, body hair etc
Describe and understand the structural domains of a steroid receptor protein, and how they contribute to the function
STEROID RECEPTOR HORMONES
- Steroid hormones cross into cell cytoplasm & bind to their receptor
- = conformational change in the nuclear receptor = activation (some nuclear receptor dimerise)
- Nuclear receptors translocate into the nucleus
- Nuclear receptors bind to specific DNA sequences (response elements) located in the promoters of steroid responsive genes.
- Steroid responsive genes are switched on and upregulated.
CHARACTERISTICS:
LBD: ligand binding domain to specific steroid hormones w/ high affinity
DBD: bind to specific DNA sequences in steroid responsive genes.
AFD: Activation - function domain = recruits gene activation machinery
(some contain both AF1 & AF2 which act toward C-terminal)
Discuss how hormones influence cancer growth and different ways this can be manipulated.
PROSTATE CANCER
- ANDROGEN RECEPTOR (AR): high chaperone association, remains in cytoplasm of luminal epithelium cells in stroma of prostate.
- testosterone is converted via 5-a-reductase into DHT (increased potency)
- ligand binding allows high affinity = dimerization = activate
- translocate into nucleus => binds w/ androgen response elements to activate transcriptional machinery to increase transcription of target gene
EXPLOITATION IN THERAPY: (inhibition of adrenal androgen production)
Testosterone used for cancer growth = increased sensitivity and dependency therefore, less testosterone = less growth/ tumour starvation/ increased apoptosis
=> targeting of AR (turning off switch) = decrease in testosterone = reduced cancer growth
- interrupt feedback loop w/ GnRH
- inhibition of 5-a-reductase in DHT production
- inhibit production of testosterone from adrenal precursors
- adrenal production of precursors travel to testes via circulation to convert to testosterone
- reduce precursors = reduced testosterone
- ABIRATERONE ACETATE (ZYTIGA): resembles target steroid intermediates which switch off adrenal androgen
- competitive androgen receptor: BICALUTAMIDE – work as anti-androgens/ androgen blockers which prevent AR binding and signalling
- abstaining correct ligand binding: a-helix 12 activates transcriptional machinery = inability to fold correctly = inability to activate
Understand the mechanisms of how resistance to hormone therapies develops
- AUTOCRINE STIMULATION: tumour becomes self sufficient and produces own hormones
- PROMISCUOUS LIGAND BINDING RECPETORS (lol): acquired mutations to alter ligand binding = receptor binding is less specific (eg: allow E2 to bind instead of testosterone
- RECEPTOR SIGNAL AMPLIFICATION:
- GROWTH FACTOR PHOSPHORYLATION: phosphorylate hormone inappropriately w/out need for ligand binding (E2-> breast cancer)
- VARIANTS IN ANDROGEN RECEPTOR : (eg: AR.v7 truncated AR - can trigger transcription without ligand binding
-HORMONE RATIONING - Cell receptor bypass: relies on different oncogenes = reduced dependence on steroids receptors
- Receptor co-factor amplification: recruited to DNA for target gene activation which increases sensitivity = continued transcription
- ligand binding domain mutation can allow drugs to act as agonist instead of antagonist => therapy withdrawal is best clinical decision.
understand the types of hormones, and
their origins in the body
STEROID HORMONE PRODUCTION
cholesterol > adrenal cortex = corticosteroid production > androgenic and estrogenic hormones released into circulation > gonadal tissue/organs (target tissues)
steroid = cholesterol
peptide hormones
tyrosine kinase hormones
define hormone
hormone is a *chemical messenger that is made by *specialist cells, usually within an *endocrine gland, and it is released into the *bloodstream to have an *effect in another part of the body.
BREAST CANCER:
- describe typical morphology
- origin of breast cancer
- specialised exocrine (apocrine) gland to provide milk
glands and ducts (duct lumen cavity)
milk production = lobes => lobules
milk travel down ducts to exit via nipple
apocrine = sections of cytoplasm break off to release contents
luminal => polarised epithelium => milk production
basal => contractile function during lactation
hormone independant phase (embryonic / pre pubescent)
estrogen drive ductal elongation (bud formation) and maintaining progesterone = duct branching - uncontrolled division and tumour development in breast tissue
cells lining milk duct, 16-20 subtypes
RISKS: age, lifestyle, family history/genetics, contraceptives, heavy drinking, HRT [BRCA 1-2]
lobules => ducts surrounded by fatty tissue (ductal breast cancer in-situ)
lobular carcinoma => LCIS = increased risk
luminal cells = E2 receptor expression
state the roles oestrogen and progesterone play in breast cancer
E2R target?
- cell proliferation, development
- bind DNA and open helix is hijacked = expression of 100s genes used in invasion and metastasis
- retain sensitivity = drive cancer growth = switch off E2R signalling = reduced cancer growth
> analysis for treatment using tissue biopsy (immunohistochemistry)
Describe E2R blocking utilised in therapy against breast cancer
FULVESTRANT (FASLODEX)
- analogue of estradiol = compete with E2 for E2R due to higher affinity
Disables AF1 and AF2 = transcriptional inactivation
Highly unstable = wears down E2R protein = degradation = no activity
TAMOXIFEN:
- works as selective estrogen receptor modulator. binds to E2R at LBD as partial agonist in uterus w/ mixed activity and antagonist behaviour in breast E2R
E2R + TAMOXIFEN = improper folding, reduced AF2 function
TYPICALLY…
- estradiol binding = deep pocket protein loop in E2R = trigger AF2 growth stimulation
- tamoxifen impedes protein loop formation due to bulky tail = unable to adopt activated conformation (only AF1 activated) = E2R partially activated which = stalemate in breast tissue E2R
Describe the potential of aromatase inhibitors
EXEMESTANE (AROMASIN) (peripheral conversion of androgens)
post menopausal estrogen production derived from androgen conversion via aromatase removing ketone group from estradiol.
aromatised (convert O group from ketone to alcohol)
TYPE 1: irreversible binding to aromatase. effect dependant on de novo synthesis of aromatase
TYPE 2: ANASTRZOLE (ARIMIDEX) contains functional group in ring structure. Interferes hydroxylation reactions by binding on haem group in cytochrome P450.
Where are aromatase enzymes found?
- adipose
- brain tissue
- skin /blood
- endometrium
- breast tissue
PROSTATE CANCER CARD:
- Describe normal prostate morphology
- State the origin of the cancer
- underneath bladder, exocrine gland, duct system to produce semen, illuminal epithileal cells and basal cells for muscular contraction. (apocrine gland)
- infertility related protastitis, BPH [benign prostatic hyperplasia]/ dysregulated prostate growth
BRCA1 & 2 Men with Lynch syndrome (also known as hereditary non-polyposis colorectal cancer, or HNPCC), a condition caused by inherited gene changes, have an increased risk
- PTEN is a phosphatase that antagonizes the phosphatidylinositol 3-kinase signalling pathway.
* As PTEN is the only known 3′phosphatase counteracting the PI3K/AKT pathway.
* Loss of PTen results in increased growth factor signalling.
State some symptoms associated with prostate cancer
- pain in urinating
- frequent urinating
- hesitating to urinate
- blood in urine
- lower back pain
- sudden urgency to urinate
What are the key steps in testosterone contributing to cancer growth?
- cholesterol (adrenal gland)
- testosterone (blood)
- DHT (cytoplasm)
- AR binding (translocate into nucleus)
- AR translocation (nucleus)
- AR + DNA binding “
- co-factor recruitment”
- AR gene activation “
= increased transcription => increased cancer growth
