Introduction To Hormone Dependent Cancers Flashcards
What is a Hormone?
- Chemical messenger made by specialist cells of an endocrine gland
- Released into the bloodstream to have an effect in another part of the body
State the endocrine glands - site of production of hormones?
- Pineal gland
- Hypothalamus
- Pituitary
- Thyroid
- Thymus
- Pancreas
- Adrenal cortex/kidneys
- Testes
- Ovaries
State the 3 classes of hormones?
- Steroids
- Lipid soluble small molecules
- Peptide / proteins OR Modified amino acids
- Amine hormones
What are all steroid hormones synthesised from and where in the body?
- in Cholestrol
- Main corticosteroids and mineralocorticoids are synthesised in the adrenal cortex
- Androgens are produced in target tissues e.g. testes and ovaries then released into the bloodstream
- Ingested or synthesised de novo in the body
State the 2 sex steroid hormones and their function?
- Testosterone: controls reproductive and supportive organs (prostate) and development of sexual characteristics in men
- Oestrogen: controls the menstrual cycle, breast tissue development, fertility, reproductive organ development and secondary sexual characteristics
How are the breasts and prostate tissue hormone dependent?
- Tissues are Influenced via steroid hormones
- Determines growth and development
- Can influence progression of cancer
Describe the general structure of a steroid hormone?
- Small lipophilic molecule with multi-ringed structure
- Enter cells by passing through plasma membrane
- Lipophilic = tending to combine with or dissolve in lipids or fats
What type of receptor does the steroid hormone bind to when entering cells?
- Nuclear Receptors
- Found in cytoplasm or nucleus
- Effects in nucleus
Describe the receptor mechanism when steroid hormone binds?
- Steroid hormones cross into the cell cytoplasm + binds to receptor
- conformational change in the nuclear receptor = activated (some dimerise)
- NRs translocate into the nucleus
- Bind to specific DNA sequences (response elements) located in the promoters of steroid responsive genes
- Steroid responsive genes are switched on and upregulated
- Increased gene expression
Describe the main parts of the nuclear receptor with its function
- Ligand binding domain: Binds specific steroid molecules with increased affinity
- DNA binding domain: Binds specific DNA sequences
- Activation function domain (AF1 & 2):Recruits gene activation machinery -> some receptors have a secondary AF2 domain towards the C-terminal
- Has a Globular structure
Why are nuclear receptors also known as ligand-activated receptors?
- The binding of steroids to the ligand binding domain -> physical restructuring of the polypeptide chains in the receptor -> activating it
Describe the mechanism of ligand-activated TF when receptor binding occurs?
- Ligand binding to the ligand binding site
- a shift in alpha - 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
- Increases gene expression
Describe the structure of the DNA binding domain with its function?
- Contains 2 zinc fingers domains: for sequence specific DNA binding
- CI Zinc finger: Specific DNA sequence binding
- CIl Zinc finger: Interacts with DNA phosphate backbone
What are the 2 possible actions that can occur to gene from a steroid hormone receptor and state examples of these genes?
- Upregulated (mostly) or downregulated
- Genes: functional tissue specific genes, cell cycle and proliferation genes, + genes involved in tissue development and differentiation
What are hormone response elements and describe a key domain within it?
- Specific DNA sequences found in the promoters of hormone responsive genes
- Palindromic: Contains zinc finger domain, binds specific HRE
How many receptors are found in the nuclear receptor super family and state similarieis + differences in their general structure
- 48
- Increased homology in DNA binding domain
- Differ in Ligand binding domain + increased differ in N-terminal activation domains
Morphology of the breast
Describe the structure of the breast and what type of a gland it is?
- Apocrine gland: produces milk, Composed of glands + ducts
- 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 ducts
- They connect + come together into larger ducts
- Exit the skin in the nipple.
What is an apocrine, exocrine and endocrine gland?
- Apocrine glands: Are a specialised exocrine gland in which a part of the cells’ cytoplasm breaks off releasing the contents - mammary gland
- Exocrine glands: Secrete substances out onto a surface or cavity, via a ductal structure
- Endocrine glands: Secrete substances directly into the bloodstream
Describe the structure of the mammary gland tissue?
- 2 cell compartment - luminal + basal
- Luminal: Form single layer of polarized epithelium around the ductal lumen - produce milk during lactation.
- Basal: Comprise of cells that do not touch the lumen -> basally oriented myoepithelial cells in contact with the basement membrane + have contractile function during lactation
State the 2 major phases in the mammary gland (breast) development?
- Hormone-independent from embryonic development up to puberty
- Hormone-dependent thereafter during puberty, menstrual cycle and pregnancy.
Describe the role of ostrogen in the normal breast?
- Estrogen, together with other hormones (e.g. growth hormone and cortisol): Increase expression of genes involved in cellular proliferation and differentiation
- Hormone-dependent mammary gland development after puberty - ductal elongation + triggers side branching.
- In the adult, estrogen allows for the maintenance of mammary gland tissue + primes the tissue for the effects of progesterone during pregnancy for milk production.
Describe the role of progesterone activity in the normal breast?
- Estrogen is primarily involved in the initial growth of breast cancer
- PG receptor gene is switched on by the estrogen receptor
- PG increase branching of the ducts
- Prolonged progesterone receptor activity i.e. during pregnancy -> increased side branching + lactogenic differentiation (together with prolactin hormone).
What is breast cancer?
- Abnormal cells in the breast begin to grow and divide in an uncontrolled way
- Eventually form tumour
- Breast cancer starts in the breast tissue (in milk ducts)
Describe aetiologie
Aet. - Age, genetic (BRCA1 + BRCA2), lifestyle
What is ductal breast carcinoma in situ?
- When cancer cells develop + remain within the ducts of the breast (‘in situ’) - DCIS
- Cancer cells have not yet developed the ability to spread outside these ducts or to other parts of the body
What is Lobular Breast Carcinoma in Situ (LCIS)?
- Uncommon condition in which abnormal cells form in the milk glands (lobules) in the breast
- LCIS isn’t cancer
- Indicates an increased risk of developing breast cancer
Describe the subtypes of breast cancer?
- Estrogen receptor + ve(75%)
- Progesterone receptor +ve or ER -ve
- Positive: Good prognosis + some PR subtypes can decrease cell growth -> PR = indicator of ostrogen activity
- ER Negative: poor prognosis -> not treated ‘hormonally’ + conventional therapies
Describe the role of Estrogen receptors in breast cancer?
- ER signalling pathway is subverted + becomes uncontrolled
- ER’s ability to bind DNA + open chromatin becomes hijacked + is used to transcribe many genes, non-coding RNAs and miRNAs
- Then governs cancer cell proliferation, controls + influences many hundreds of genes involved in metastasis, invasion and adhesion.
What can be used as a potential vulnerability for the treatment of Breast cancer?
Target ER -> Switch off ER signalling -> Cancer growth inhibited
State how ostrogen action can be inhibited and state 3 drug examples
- Block the binding to the receptor OR degrade ER protein
- Fulvestrant (faslodex)
- Tamoxifen
- Aromatase inhibitors
Describe fulvestrant and its mechanism of action?
- Fulvestrant: Analogue of Oestrogen
- Fulvestrant inhibits binding of Oestrogen to ER via higher affinity
- F-ER binding impairs receptor dimerisation + energy-dependent nucleo-cytoplasmic shuttling
- Blocks nuclear localisation of the receptor
- If enters the nucleus = transcriptionally inactive as AF1 and AF2 are disabled -> Unstable complex -> Accelerated degradation of the ER protein.
Describe tamoxifen and its mechanism of action?
- A Selective Estrogen Receptor Modulator
- Tamoxifen binds ER at the ligand binding site
- Partial agonist but does not cause the full activation of ER
- T bound ER does not fold properly + the AF2 domains don’t function( AF1 active)
- It has a mixed activity
- It activates ER in the uterus and liver, but acts as an antagonist in breast tissue
Aromatase inhibitor
When ovaries are no longer functional in postmenopausal woman, state other sources of ostrogen?
- Conversion of androgens to Oestrogen via aromatase enzyme -> Ketone group to alcohol
State the 2 types of aromastase inhibitors
- Exemestane
- Anastrozole
Describe the exemestane mechanism of action
androgen analogues + bind irreversibly to aromatase -> “suicide inhibitors” -> duration of inhibitory effect = rate of de novo synthesis of aromatase
Describe the anastrozole mechanism of action
- Contain a functional group within the ring structure that binds the heme iron of the cytochrome P450
- Interferes with hydroxylation reactions
Provide a summary of breast cancer
- Breast cancer is derived from a hormonally sensitive tissue, and remains responsive and reliant on estrogen for growth.
- Blocking estrogen action via competitive inhibitors and reducing estrogen synthesis is an unique avenue that can be exploited to treat breast cancer
- In many cases anti-estrogen therapy is very useful, but 1/3 may develop endocrine resistance, and relapse within 5 years, after which conventional chemotherapy may be used (i.e. non hormonal)
Morphology of prostate gland
What is the main function of the prostate gland?
- Produce prostatic fluid
- Creates semen when mixed with the sperm produced via testes
What type of gland is the prostate?
Exocrine
Describe the phases involved with prostate gland development?
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 + prostate cancer
State prostate abnormalites that can arise + key symptoms?
- Inflammation (via infection) -> Prostatitis (linked to infertility)
- Dysregulated growth of prostate - Benign prostatic hyperplasia (benign) + prostate cancer (malignant)
- Symptoms: Frequent trips to urinate, trouble urinating, blood in the urine (rare)
Describe 3 methods used to detect prostate cancer?
- Digital rectal examination (DRE)
- Prostate-specific antigen test: Blood sample - antibody-based assay
- Ultrasound - detect tumour outside prostate capsule
Describe 3 ways prostate cancer can be staged and outline them? Weird one
- T1 : small, localised tumour -> T2: palpable tumour -> T3: escape from prostate gland -> T4: Local spread to pelvic region
- N+: Tumour in lymph nodes -> NO: No cancer cells found in any lymph nodes -> N1: 1 positive lymph node < 2cm across -> N2 -> 1 positive lymph node or 1 between 2-5cm across -> N3 -> Any positive lymph node > 5 cm across
- Metastatic -> M1a - Non-regional lymph nodes -> M1b - bone -> M1c - other sites
What system is used for prostate cancer grading?
- The Gleason grading system evaluate the prognosis of men using prostate biopsy samples
- Predicts prognosis + helps guide therapy
- Cancers with increased Gleason score = more aggressive + worse prognosis
State 4 treatments for prostate cancer with the conditions?
- “Watchful waiting”: Low grade tumour, older patients
- Radical prostatectomy: Stage T1 or T2
- Radical radiotherapy: External up to T3 (spread past capsule) + Internal implants (brachytherapy) for T1/2
- Hormone therapy: + prostatectomy or radical radiotherapy + Metastatic prostate cancer
What factors are used for when deciding to choose either ‘watchful weighting’ or ‘active surveillance’ as a therapy for prostate cancer?
- Watchful waiting
- Recommended for older men when it’s unlikely the cancer will affect their natural lifespan
- If the cancer is early stages + not causing symptoms
- Delay treatment + wait to see if any symptoms of progressive cancer develop.
What factors are used for when deciding to choose either ‘watchful weighting’ or ‘active surveillance’ as a therapy for prostate cancer?
- Active surveillance
- Avoid unnecessary treatment of harmless cancers + providing timely treatment for men who need it
- involves having regular PSA tests, MRI scans + biopsies to ensure any signs of progression are found early
State risk factors for prostate cancer?
- Age
- Race/ethnicity
- Geography
- Family history
- Gene changes (increased BRCA1 OR BRCA2, lynch syndrome/hereditary non-polyposis colorectal cancer)
State genes associated with prostate cancer?
BRCA1 mutation + PTen loss
Describe the PTen gene?
- Phosphatase antagonizes the phosphatidylinositol 3-kinase signalling pathway
- Only known 3’phosphatase counteracting the PI3K/AKT pathway
- Loss of PTen = increased growth factor signalling
What fusion gene is most present in prostate cancer? VD
- TMPRSS2-ERG fusion gene -> AR now drives proto-oncogene ERG -> Inappropriate gene activation
What hormone is the growth and development of the prostate gland is dependent on?
- Testosterone (androgens)
- Produced in testes
Describe the androgen receptor signalling pathway?
- Androgen receptors is located in the cytoplasm
- Testosterone is converted to Dihydrotestosterone as it crosses into the prostate
- Binds to Androgen receptor
- Dimerization of receptor
- DNA binding
- Co-activator recruitment
- Increased target gene
- Cell growth
What can be used as a potential vulnerability for the treatment of prostate cancer?
Androgens -> Switch off androgen receptor signalling -> Switch off cancer growth
State how testosterone synthesis can be inhibited?
- Abiraterone acetate ->Prevents production of adrenal androgens via cholestrol
- Disrupt hormone production feedback loop -> Inhibit GRH -> Goserelin (super agonist) OR abarelix (anatagonist) -> decreased testosterone production in testes
State how inhibition of testosterone conversion to DHT can occur?
- 5-alpha reductase inhibitors (5-a converts T - DHT) -> finasetride + dutsteride (avodart) -> benign prostate hyperplasia
Describe how androgen binding to the receptor can be inhibited?
- Competitive anti-androgens/ androgen blockers - compete for active site -> Bicalutamide, Enzalutamide, Flutamide + Nilutamide -> Inactive TF -> open unliganded receptor or incorrect binding (AR helix 12 cannot fold over)
Summarise prostate cancer
- Prostate cancer is derived from a hormonally sensitive tissue, and remains responsive and reliant on androgens for growth
- Blocking androgen action via competitive inhibitors and reducing androgen synthesis is an unique avenue that can be exploited to treat prostate cancer
