Hormone dependant breast cancer Flashcards
What is a hormone?
A 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.
Describe how cholesterol is modified to produce other hormones
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What governs the growth and development of the gonadal tissue?
Steroid production and influence
When cancers arise in breast or prostate tissues – the steroid hormones can still influence how the cells grow and function, and consequently how the disease develops and progresses. The dependence of these tissues on steroids can be exploited when it comes to the treatment of these cancers i.e. the blocking of steroid action as a therapy for cancer.
Describe the action of steroid hormones
- Steroid hormones cross into the cell 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 steroid response elements located in the promoters of steroid responsive genes.
- Steroid responsive genes are switched on and upregulated.
What is the ligand binding domain?
What is the DNA binding domain?
What is the function domain?
Ligand binding domain (LBD) binds specific steroid molecules with high affinity; the binding of steroids to the ligand binding domain causes a physical restructuring of the polypeptide chains in the receptor, activating it
DNA binding domain (DBD) binds specific DNA sequences; the DNA binding domain contains 2 zinc fingers domains, which are essential for sequence specific DNA binding and help recognise hormone response elements
Activation function domain (AF1 & 2) recruits gene activation machinery, some receptors have a secondary AF2 domain towards the C-terminal.
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 is the breast?
• The breast (mammary gland) is a specialised type of exocrine gland called an apocrine gland that produces the milk used to feed an infant
What is the breast composed of and what does it produce?
- The breast is composed of glands and ducts, which produce the fatty breast milk.
- The milk-producing part of the breast is organized into 15 to 20 sections, called lobes.
- Within each lobe are smaller structures, called lobules, where milk is produced.
- The milk travels through a network of tiny tubes called ducts. The ducts connect and come together into larger ducts, which eventually exit the skin in the nipple.
Whats exocrine and endocine?
apocine
Exocrine glands – secrete substances out onto a surface or cavity, via a ductal structure.
Endocrine glands – secrete substances directly into the bloodstream
Apocrine glands – are a specialised exocrine gland in which a part of the cells’ cytoplasm breaks off releasing the contents.
What is the mammalian epithelium composed of?
- 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
Describe the role of eoestrogen
Estrogen, together with other hormones (e.g. growth hormone and cortisol) drives the 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 the adult estrogen allows for the maintenance of mammary gland tissue, and also primes the tissue for the effects of progesterone during pregnancy for milk production.
Estrogen is primarily involved in the initial growth of breast cancer The progesterone receptor gene is switched on by the estrogen receptor, and 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).
When does breast cancer occur?
Breast cancer occurs when abnormal cells in the breast begin to grow and divide in an uncontrolled way and eventually form a tumour.
Breast cancer starts in the breast tissue, most commonly in the cells that line the milk ducts of the breast.
When cancer cells develop within the ducts of the breast but remain within the ducts (‘in situ’), it is called DCIS. The cancer cells have not yet developed the ability to spread outside these ducts into the surrounding breast tissue or to other parts of the body.
Lobular carcinoma in situ (LCIS) is an uncommon condition in which abnormal cells form in the milk glands (lobules) in the breast; not cancer but could be sign of developing breast cancer
The majority of breast cancers arise in the luminal cells which express ER; the signalling pathway becomes uncontrolled so if we switch off ER signalling we can switch off cancer growth:
What is Fulvestrant?
Fulvestrant , an analogue of estradiol, competitively inhibits binding of estradiol to the ER, with a 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.
What does Tamoxifen do?
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 therefore said to be a Selective Estrogen Receptor Modulator (SERM) Tamoxifen bound ER does not fold properly and the AF2 domains do not function
What are Aromatase inhibitors
What are the two types?
Aromatase inhibitors prevent conversion of androgens into oestrogens:
Type 1 inhibitors, like exemestane (Aromasin ©), 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 (Arimidex ©), contain a functional group within the ring structure that binds the heme iron of the cytochrome P450, interfering with the hydroxylation reactions.
What is the function of the prostate gland?
- The main function of the prostate is to produce prostatic fluid that creates semen when mixed with the sperm produced by the testes.
- The prostate gland is an exocrine (apocrine) gland located just underneath the bladder in the abdomen,
- Luminal epithelial cells is where prostatic fluid is produced
