Breast and prostate cancer Flashcards
What are all steroid hormones synthesised from
Cholesterol
What is the the link between steroid hormones and breast/ prostate cancer
the steroid hormones can still influence the growth and development. The dependence of these tissues on steroid can be exploited and used as an anti-cancer therapy.
Steroid hormone action
–Steroid hormones cross into the cell ( due to its lipophilic structure) cytoplasm where
they will bind to their receptor
–Binding to the receptor causes a conformational
change in the nuclear receptor, causing it to become
activated (some nuclear receptor dimerise at this
point)
–Nuclear receptors then translocate into the nucleus
–Nuclear receptors bind to specific DNA sequences
called response elements located in the promoters of
steroid responsive genes.
–Steroid responsive genes are switched on and
upregulated.
what are the 3 key characteristics of nuclear receptors
Ligand binding domain (LBD) ----Binds specific steroid molecules with high affinity DNA binding domain (DBD) ----Binds specific DNA sequences Activation function domain (AFI & 2) ----Recruits gene activation machinery
Steps in Ligand Activated Transcription Factors
- Ligand binding to the ligand binding site
causes a shift in an a—helix, activating the
receptor. - Receptor dimerises, moves into the nucleus
and binds to specific DNA sequences - Receptor then recruits DNA modifying
enzymes e.g. histone deacetylases, other
transcription factors and RNA polymerase to
promoters of hormone responsive genes.
what does the DNA binding domain contain which helps with specific DNA binding and interaction
The DNA binding domain contains 2 zinc fingers domains, which are essential for sequence specific DNA binding.
-Cl Zinc finger
Specific DNA
sequence binding
-Cll Zinc finger
Interaction with the
DNA phosphate backbone
what are hormone response elements
Hormone Response Elements are specific DNA sequences
found in the promoters of hormone responsive genes.
Many are palindromic
how many nuclear receptor genes are in humans
48
similarity of steroid receptors
Receptors have a high homology in the DNA binding domain, and differ in ligand binding
domains, and differ significantly in N-terminal activation domains
what are the main five steroid receptors , their abbreviation and respective ligands
1) Oestrogen Receptor (ER)- oestradiol, estrone, estriol
2) Androgen Receptor (AR)- androstenedione, testosterone, dihydrotestosterone
3) Progesterone Receptor (PR)- progesterone, pregnenolone
4) Glucocorticoid Receptor (GR) -cortisol and cortisone
5) Mineralocorticoid Receptor (MR) -aldosterone
What kind of gland is the breast
specialised form of exocrine gland called Apocrine gland
the milk producing part of the breast is organised into how many section and what are they called
15-20
lobes
what are the structures within each lobes called
lobules
what are the 2 cell compartment in the mammary epithelium
- Luminal — form a single layer of polarized epithelium around the ductal lumen, luminal cells produce milk during lactation.
- Basal — comprise of the cells that do not touch the lumen, basally oriented myoepithelial cells in contact with the basement membrane, have contractile function during lactation
What is the function of ER in the normal breast tissue
- Oestrogen, together with other hormones (e.g. growth hormone and cortisol) drives the expression of genes involved in cellular proliferation and differentiation
- In the adult oestrogen allows for the maintenance of mammary gland tissue, and also primes the tissue for the effects of progesterone during pregnancy for milk production.
what is the progesterone activity in the normal breast
- The progesterone receptor gene is switched on by the oestrogen receptor
- Progesterone increases the branching of the ducts
- Prolonged progesterone receptor activity i.e. during pregnancy, leads to more side branching and lactogenic differentiation (together with prolactin hormone).
what are some of the risk factors to breast cancer
-Age - The risk for breast cancer increases with age; most breast cancers are diagnosed after age 50.
-Genetic mutations to certain genes, such as BRCAI and BRCA2.
• Reproductive history. Early onset of menstrual cycle before 12yrs and starting menopause after 55yrs expose women longer to hormones.
• Previous treatment using radiation therapy to the chest or breasts (e.g. treatment for lymphoma) before age 30 have a higher risk of getting breast
cancer later in life.
-not being physically active
-overweight or obesity
taking hormones or contraceptive pills
-alcohol
Ductal breast carcinoma in situ (DCIS)
Cancer cells develop within the ducts of the breast but remains within the ducts- have not gained the ability to spread
Lobular Breast Carcinoma in Situ (LCIS)
Lobular carcinoma in situ (LCIS) is an uncommon condition in which abnormal cells form in the milk glands (lobules) in the breast. LCIS isn't cancer. But being diagnosed with LCIS indicates that there could be an increased risk of developing breast cancer.
where does the majority of breast cancer arise
luminal cells, these cells express ER
ER positive and negative breast cancer
The majority of breast cancers are ER positive and have a good prognosis, however the remainder are ER-ve and
have a relatively poor prognosis.
ER-ve breast cancers cannot be treated ‘hormonally’ and patients are given more conventional therapies.
what is fulvestrant
aka faslodex
is an analogue of oestradiol, which competitively inhibits binding of oestradiol to the ER
• 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 AFI and AF2
are disabled.
• The fulvestrant—ER complex is unstable, resulting in
accelerated degradation of the ER protein.
What Tamoxifen
Tamoxifen binds the ER at the ligand binding site.
Tamoxifen is a partial agonist but does not cause the full activation of ER.
It has a mixed activity— it activates ER in the uterus and liver, but acts as an antagonist in breast tissue.
Tamoxifen is a Selective Estrogen Receptor Modulator (SERM).
Tamoxifen bound ER does not fold properly and the AF2 domains do not function
Aromatase inhibitors (what are the 2 types)
Type 1 inhibitors, like exemestane, are
androgen analogues and bind irreversibly to aromatase, so
they are also called “suicide inhibitors”. The duration of
inhibitory effect is primarily dependent on the rate of de
novo synthesis of aromatase.
Type 2 inhibitors, like anastrozole, contain a
functional group within the ring structure that binds the
heme iron of the cytochrome P450, interfering with the
hydroxylation reactions.
