intro to hormone dependent cancers Flashcards
define hormone
chemical messenger made by specialist cells, usually within endocrine glands and released into bloodstream to have an effect in another part of the body
where are hormones produced
pineal gland hypothalamus pituitary thyroid pancreas adrenal cortex testes/ovaries
3 main types of hormones
steroids = lipid soluble small molecules
peptide
modified amino acids
describe steroid hormones
all synthesised from cholesterol
basic 4 ring steroid backbone structure
adrenal cortex = synthesises corticosteroids and mineralcorticosteroids
e.g androgen, testosterone, estradiol
work systemically, have effect on several tissues
females oestrogen
male testosterone
describe sex hormones
responsible for sexual dimorphism between males and females
development of secondary sexual characteristics e.g growth spurt/body hair
key characteristics of nuclear receptors
- 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
describe ligand activated TFs
- ligand binding to LBS = stiff in alpha helix = activates receptor
- receptor dimerises, moves into nucleus and binds specific DNA sequences
- receptor recruits DNA modifying enzymes e.g. histone deacetylases
describe 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 DNA phosphate backbone
hormone responsive genes
genes may be upregulated by steroid hormone receptor
some genes may be downregulated
genes include functional tissue specific genes, cell cycle, proliferation genes, gene involved in tissue development and differentiation
what are hormone response elements
specific DNA sequences found in promoters of hormone responsive genes. many are palindromic
describe nuclear receptor family
48 nuclear receptor genes
share common domain structure and arise from common evolutionary ancestors
share structure that is activated by ligand binding
describe the breast
apocrine gland, produces milk
milk producing part = 15-20 sections = lobes
within lobes = lobules where milk is produced
milk travels through ducts
apocrine gland
exocrine gland = secretes substances out
endocrine = secretes substances directly to bloodstream
apocrine = specialised exocrine gland, cell cytoplasm
breaks of releasing contents
describe mammary gland tissue structure
2 compartments
- luminal = single layer of polarised epithelium around ductal lumen, luminal cells produce milk during lactation
basal = cells that don’t touch lumen basally orientated myoepithelial cells in contact with basement membrane, have contractile function during lactation
describe 2 major phases during mammary gland development
- hormone independent from embryonic development up to puberty
- hormone dependent during puberty, menstrual cycle and pregnancy
what does oestrogen do in adults
allows maintenance of mammary gland tissue and primes tissue for effects of progesterone during pregnancy for milk production
describe breast cancer
when abnormal cells in breast begin to grow and divide in uncontrolled way and form a tumour
begins in breast tissue, in cells that line milk ducts of breast
1/8 women develop breast cancer in their lifetime
main risks = age, lifestyle, genetic familial factors
taking hormones/hormone replacement during menopause can increase risk
describe ductal breast carcinoma in situ
cancer cells develop within ducts of breast but remain within ducts
cancer cell hasn’t developed ability to spread outside ducts into surrounding breast tissue
describe lobular breast carcinoma in situ
uncommon condition in which abnormal cells form in milk glands of breast = either ER positive or negative
majority of breast cancer develops from luminal cells = express ER+ve have good prognosis
if negative = poor prognosis
explain ER in breast cancer
ER controls cell proliferation/development and differentiation in highly controlled manner
in breast cancer = ER pathway becomes uncontrolled and no longer able to bind to dna/open chromating
ER governs cancer cell proliferation, controls and influences genes involved in metastasis, invasion and adhesion
switch off ER signalling = switch off cancer growth
inhibiting estrogen action - how?
blocking estrogen competitively binding to receptor and degrading ER protein
no ER signalling = no breast cancer cell growth
fulvestrant
analogue of estradiol
competitively inhibits binding of estradiol to ER, with binding affinity that is 89% of estradiol
fulvestrant = ER binding impairs receptor dimerisation = blocks nuclear localization of receptor
fulvestrant = ER complex in nucleus = transcriptionally inactive as AF1/2 are disabled
tamoxifen
binds ER at ligand binding site
partial agonist but does not cause full activation of ER
has mixed activity = activates ER in uterus and liver, acts as antagonist in breast tissue
is a selective estrogen receptor modulator
describe aromatase inhibitors
ovaries no longer functional in post menopausal women = source of estrogen comes from peripheral conversion of androgens by aromatase enzyme
present in multiple organs incl adipose tissue/brain tissue/blood vessels
androgens are hormones e.g testosterone/adrenal androgens
