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Molecular Basis Of Disease > Introduction To Hormone Dependent Cancers > Flashcards

Introduction To Hormone Dependent Cancers Flashcards

1
Q

What is a Hormone?

A
  • Chemical messenger made by specialist cells of an endocrine gland
  • Released into the bloodstream to have an effect in another part of the body
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2
Q

State the endocrine glands - site of production of hormones?

A
  • Pineal gland
  • Hypothalamus
  • Pituitary
  • Thyroid
  • Thymus
  • Pancreas
  • Adrenal cortex/kidneys
  • Testes
  • Ovaries
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3
Q

State the 3 classes of hormones?

A
  • Steroids
  • Lipid soluble small molecules
  • Peptide / proteins OR Modified amino acids
  • Amine hormones
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4
Q

What are all steroid hormones synthesised from and where in the body?

A
  • 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
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5
Q

State the 2 sex steroid hormones and their function?

A
  • 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
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6
Q

How are the breasts and prostate tissue hormone dependent?

A
  • Tissues are Influenced via steroid hormones
  • Determines growth and development
  • Can influence progression of cancer
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7
Q

Describe the general structure of a steroid hormone?

A
  • 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
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8
Q

What type of receptor does the steroid hormone bind to when entering cells?

A
  • Nuclear Receptors
  • Found in cytoplasm or nucleus
  • Effects in nucleus
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9
Q

Describe the receptor mechanism when steroid hormone binds?

A
  • 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
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10
Q

Describe the main parts of the nuclear receptor with its function

A
  • 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
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11
Q

Why are nuclear receptors also known as ligand-activated receptors?

A
  • The binding of steroids to the ligand binding domain -> physical restructuring of the polypeptide chains in the receptor -> activating it
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12
Q

Describe the mechanism of ligand-activated TF when receptor binding occurs?

A
  • 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
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13
Q

Describe the structure of the DNA binding domain with its function?

A
  • 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
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14
Q

What are the 2 possible actions that can occur to gene from a steroid hormone receptor and state examples of these genes?

A
  • Upregulated (mostly) or downregulated
  • Genes: functional tissue specific genes, cell cycle and proliferation genes, + genes involved in tissue development and differentiation
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15
Q

What are hormone response elements and describe a key domain within it?

A
  • Specific DNA sequences found in the promoters of hormone responsive genes
  • Palindromic: Contains zinc finger domain, binds specific HRE
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16
Q

How many receptors are found in the nuclear receptor super family and state similarieis + differences in their general structure

A
  • 48
  • Increased homology in DNA binding domain
  • Differ in Ligand binding domain + increased differ in N-terminal activation domains
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17
Q

Morphology of the breast
Describe the structure of the breast and what type of a gland it is?

A
  • 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.
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18
Q

What is an apocrine, exocrine and endocrine gland?

A
  • 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
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19
Q

Describe the structure of the mammary gland tissue?

A
  • 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
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20
Q

State the 2 major phases in the mammary gland (breast) development?

A
  • Hormone-independent from embryonic development up to puberty
  • Hormone-dependent thereafter during puberty, menstrual cycle and pregnancy.
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21
Q

Describe the role of ostrogen in the normal breast?

A
  • 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.
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22
Q

Describe the role of progesterone activity in the normal breast?

A
  • 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).
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23
Q

What is breast cancer?

A
  • 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)
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24
Q

Describe aetiologie

A

Aet. - Age, genetic (BRCA1 + BRCA2), lifestyle

25
Q

What is ductal breast carcinoma in situ?

A
  • 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
26
Q

What is Lobular Breast Carcinoma in Situ (LCIS)?

A
  • 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
27
Q

Describe the subtypes of breast cancer?

A
  • 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
28
Q

Describe the role of Estrogen receptors in breast cancer?

A
  • 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.
29
Q

What can be used as a potential vulnerability for the treatment of Breast cancer?

A

Target ER -> Switch off ER signalling -> Cancer growth inhibited

30
Q

State how ostrogen action can be inhibited and state 3 drug examples

A
  • Block the binding to the receptor OR degrade ER protein
  • Fulvestrant (faslodex)
  • Tamoxifen
  • Aromatase inhibitors
31
Q

Describe fulvestrant and its mechanism of action?

A
  • 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.
32
Q

Describe tamoxifen and its mechanism of action?

A
  • 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
33
Q

Aromatase inhibitor
When ovaries are no longer functional in postmenopausal woman, state other sources of ostrogen?

A
  • Conversion of androgens to Oestrogen via aromatase enzyme -> Ketone group to alcohol
34
Q

State the 2 types of aromastase inhibitors

A
  • Exemestane
  • Anastrozole
35
Q

Describe the exemestane mechanism of action

A

androgen analogues + bind irreversibly to aromatase -> “suicide inhibitors” -> duration of inhibitory effect = rate of de novo synthesis of aromatase

36
Q

Describe the anastrozole mechanism of action

A
  • Contain a functional group within the ring structure that binds the heme iron of the cytochrome P450
  • Interferes with hydroxylation reactions
37
Q

Provide a summary of breast cancer

A
  • 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)
38
Q

Morphology of prostate gland
What is the main function of the prostate gland?

A
  • Produce prostatic fluid
  • Creates semen when mixed with the sperm produced via testes
39
Q

What type of gland is the prostate?

A

Exocrine

40
Q

Describe the phases involved with prostate gland development?

A

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

41
Q

State prostate abnormalites that can arise + key symptoms?

A
  • 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)
42
Q

Describe 3 methods used to detect prostate cancer?

A
  • Digital rectal examination (DRE)
  • Prostate-specific antigen test: Blood sample - antibody-based assay
  • Ultrasound - detect tumour outside prostate capsule
43
Q

Describe 3 ways prostate cancer can be staged and outline them? Weird one

A
  • 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
44
Q

What system is used for prostate cancer grading?

A
  • 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
45
Q

State 4 treatments for prostate cancer with the conditions?

A
  • “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
46
Q

What factors are used for when deciding to choose either ‘watchful weighting’ or ‘active surveillance’ as a therapy for prostate cancer?

A
  • 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.
47
Q

What factors are used for when deciding to choose either ‘watchful weighting’ or ‘active surveillance’ as a therapy for prostate cancer?

A
  • 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
48
Q

State risk factors for prostate cancer?

A
  • Age
  • Race/ethnicity
  • Geography
  • Family history
  • Gene changes (increased BRCA1 OR BRCA2, lynch syndrome/hereditary non-polyposis colorectal cancer)
49
Q

State genes associated with prostate cancer?

A

BRCA1 mutation + PTen loss

50
Q

Describe the PTen gene?

A
  • Phosphatase antagonizes the phosphatidylinositol 3-kinase signalling pathway
  • Only known 3’phosphatase counteracting the PI3K/AKT pathway
  • Loss of PTen = increased growth factor signalling
51
Q

What fusion gene is most present in prostate cancer? VD

A
  • TMPRSS2-ERG fusion gene -> AR now drives proto-oncogene ERG -> Inappropriate gene activation
52
Q

What hormone is the growth and development of the prostate gland is dependent on?

A
  • Testosterone (androgens)
  • Produced in testes
53
Q

Describe the androgen receptor signalling pathway?

A
  • 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
54
Q

What can be used as a potential vulnerability for the treatment of prostate cancer?

A

Androgens -> Switch off androgen receptor signalling -> Switch off cancer growth

55
Q

State how testosterone synthesis can be inhibited?

A
  • 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
56
Q

State how inhibition of testosterone conversion to DHT can occur?

A
  • 5-alpha reductase inhibitors (5-a converts T - DHT) -> finasetride + dutsteride (avodart) -> benign prostate hyperplasia
57
Q

Describe how androgen binding to the receptor can be inhibited?

A
  • 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)
58
Q

Summarise prostate cancer

A
  • 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

Molecular Basis Of Disease (30 decks)

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