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molecular basis of disease > intro to hormones > Flashcards

intro to hormones Flashcards

1
Q

Define a hormone

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
  • hormones can be chemicals, peptides or proteins
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2
Q

Where are hormones produced?

A
  • pineal gland = melatonin
  • hypothalamus= TRH, GnRH
  • pituitary = ACTH, TSH, LH, FSH,GH
  • thyroid =thyroxine
  • thymus = thymosin
  • pancreas = insulin
  • adrenal glands = adrenaline
  • testis = testosterone
  • ovaries = oestrogen
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3
Q

What are 3 main classes of hormones?

A
  1. steroids - lipid soluble small molecules , eg: testosterone
  2. peptide/protein , eg: insulin
  3. modified amino acids/amine hormones, eg. adrenaline
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4
Q

What is the precursor of steroid hormones?

A
  • cholesterol

- cholesterol has basic 4 ring backbone structure

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5
Q

How are steroids synthesised?

A
  • all steroids are synthesised from cholesterol, either ingested or synthesised de novo in body
  • cholesterol -> adrenal cortex -> gonadal tissues
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6
Q

What are examples of steroid hormones?

A
  • androgen (testosterone)
  • estrogen (estradiol)
  • progesteron
    (progesterone)
  • corticosteroid (cortisol)
  • mineralocorticoid( (aldosterone)
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7
Q

What are sex hormones responsible for?

A
  • these are responsible for sexual dimorphism between males and females
  • the development of secondary sexual characteristics, eg: the growth spurt during puberty, body hair, gonadal development, voice change, breast growth and accessory organs of the reproductive organs of reproductive organs eg. the prostate in men.
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8
Q

What are effects of steroid hormones?

A

females:
-oestrogen controls menstrual cycle, and breast tissue development, fertility, and reproductive organ development, secondary sexual characteristics - body hair etc.
males:
-testosterone controls reproductive and supportive organs (prostate), development of sexual characteristics in men, eg. deepening voice, body hair etc.

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9
Q

what is the role of hormones in cancer?

A
  • when cancer arise in breast or prostate tissues - steroid hormones can still influence how the cells grow and function, and consequently how disease develops and progresses.
  • The dependence of these tissues on steroids can be exploited when it comes to the treatment of these cancers, ie: the blocking of steroid action as a therapy for cancer.
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10
Q

What is the mechanism of action of steroid hormones?

A
  • once the steroid hormones enter the cells, they bond to receptors.
  • These receptors are known as nuclear receptors - as they have their effects in the nucleus, however they may be found in cytoplasm initially.
  • steroid hormones circulates in blood and bc of its lipophilic it can enter the cell and bind to its nuclear receptor in cytoplasm.
  • conformation change occurs in the receptor after steroid binding and causes the steroid-receptor dimer to translocate/ enter the nucleus.
  • in the nucleus steroid receptor binds to DNA at specific sequences called steroid response elements (SRE), these are short sequence of DNA found in the promoter regions of steroid responsive genes.
  • steroid responsive genes are switched on and unregulated.
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11
Q

What are key characteristics of nuclear receptor?

A
  1. ligand binding domain (LBD)
    - binds specific steroid molecules with high affinity
  2. DNA binding domain (DBD)
    - binds specific DNA sequences
  3. Activation function domain (AF1 &2)
    - recruits gene activation machinery, some receptors have secondary AF2 domain towards the C-terminal.
    - when receptors bind to steroid hormones they are activated thus called ligand -activated receptors

-the binding of steroids to the ligand binding domain causes a physical restructuring of the polypeptide chains in the receptor, activating it.

=> the same basic domains and structure are shared with many of the major nuclear receptors.

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12
Q

What happens once Ligand (steroid) binds to ligand binding domain (on nuclear receptor)?

A
  1. Ligand binding to the ligand binding site causes a shift in an alpha -helix, activating the receptor
  2. Receptor dimerises, moves into nucleus and binds to specific DNA sequences
  3. Receptor then recruits DNA modifying enzymes eg: histones deacetylases, other transcription factors and RNA polymerase to promoters of hormones responsive genes.
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13
Q

Hormone responsive genes

A
  • many hundreds of genes may be upregulated by a steroid hormone receptor.
  • some genes may be down regulated
  • genes include functional tissue specific genes, cell cycle and proliferation genes, and genes involved in tissue development and differentiation.
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14
Q

nuclear receptor super family

A
  • these are 48 nuclear receptor genes in humans
  • all share a common domain structure and arise from a common evolutionary ancestor.
  • they all share a structure that is activated by ligand binding
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15
Q

What type of gland is the breast?

A

-apocrine gland :
is a specialised type of exocrine gland in which a part of the cells cytoplasm breaks off releasing the contents.
- Exocrine glands - secretes substances out onto a surface or cavity, via ductal structure.

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16
Q

Endocrine glands

A

-secrete substances directly into the bloodstream.

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17
Q

What is the mammary gland?

A
  • located in the breasts of females that is responsible for lactation or production of milk.
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18
Q

What are the two compartments of mammary gland tissue structure?

A
  1. luminal - form a single layer of polarised epithelium around the ductal lumen, luminal cells produce milk during lactation.
  2. 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.
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19
Q

What are the two major phases that can be distinguished in mammary gland development?

A
  • hormone -independent from embryonic development up to puberty
  • hormone - dependent thereafter during puberty, menstrual cycle and pregnancy
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20
Q

What is the function of estrogen receptors(ER) in normal breast?

A
  • 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 branching
  • in adult estrogen allows for maintenance of mammary gland tissue, and also primes the tissue for effects of progesterone during pregnancy for milk production.
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21
Q

What are hormones involved in different stages of development of breast tissue?

A
  1. estrogen (puberty)
    - formation of terminal end buds
    - ductal elongation
  2. Progesterone (adult virgin)
    - ductal elongation and side branching
  3. prolactin (pregnancy)
    - alveologenesis and lactogenic differentiation
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22
Q

What are main risk factors of breast cancer?

A
  • smoking
  • familial
  • age
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23
Q

Breast cancer aetiology

A
  1. Age - increased risk after 50
  2. genetic mutation - BRCA1 and BRCA2, these give higher risk of breast and ovarian cancer.
  3. reproductive history- early menstruation (<12 y/o) and later menopause (>55) expose women to hormones for longer,
  4. Previous treatment using radiation therapy to the chest or breast.
  5. overweight
  6. contraceptive
  7. alcohol
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24
Q

Define ductal breast carinoma in situ (DCIS)

A
  • when cancer cells develop within the ducts of the breast but remain within ducts (‘in situ-)
  • cancer cells have not yet developed the ability to spread outside these ducts into the surrounding breast tissue or other parts of the body.
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25
Q

Define lobular carcinoma in situ (LCIS)

A
  • abnormal cell forms in milk glands (lobules)
  • LCIS isnt cancer!
  • being diagnosed with LCIS increases risk of developing breast cancer.
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26
Q

Where do majority of breast cancer arise?

A
  • luminal cells which express ER.
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27
Q

What does ER+ and ER- mean?

A
  • majority of breast cancers are ER + which means they can be diagnosed easily (good prognosis)
  • some ER- cancers have poor prognosis and need to be treated with more conventional therapies.
28
Q

What are some tumour subtypes?

A
  1. luminal A
  2. luminal B
  3. HER2+
  4. Triple negative
29
Q

How does ER activity change in breast cancer?

A
  • in normal breast ER controls functions such as cell proliferation. development and differentiation in a highly controlled manner.
  • However, in breast cancer, the ER signalling pathway is subverted and becomes uncontrolled.
  • ER ‘s ability to bind DNA and open chromatin becomes hijacked and is used to transcribe many genes, non - coding RNAs and miRNAs.
  • ER then governs cancer cell proliferation, and controls and influences many hundreds of genes involved in metastasis., invasion and adhesion.
30
Q

Why are progesterone targeting used in breast cancer therapy?

A

=> progesterone receptors are good indicators of estrogen activity, progesterone receptor is a estrogen dependent gene so are good target for breast cancer therapy.
=> mammary gland is an oestrogen sensitive and dependent tissue, and oestrogen are key driver of breast cancer growth so we can exploit this for treatment:
-switch off ER signalling, switch off cancer growth.

31
Q

Inhibiting ER signalling

A

Biopsy samples are often analysed for ER expression. 75% of all breast cancers are ER+ve
=> women are candidates for specific treatments that block ER activity.

32
Q

How do oestrogen receptor work?

A
  1. ostrogen binds to ER at ligand binding site
  2. oestrogen translocates into nucleus and binds to DNA
  3. this recruits proteins of genes : coactivator 1, coactivator 2, RNA pol
  4. AF1 and AF2 activated and causes full gene transcription leading to breast cancer growth.
33
Q

How can we inhibit oestrogen action pharmaceutically?

A
  • blocking oestrogen binding to receptor - and degrading ER protein.
  • no ER signalling - no breast cancer cell growth.
34
Q

What are examples of oestrogen inhibitor drugs?

A

=> Fulvestrant (Faslodex)
=>Tamoxifen
=>aromatase inhibitors

35
Q

How does Fulvestrant work?

A
  • analogue of oestrogen
  • competitively inhibits binding of estradiol to the ER, with a binding affinity that is 89% that of estradiol.
  • 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.
36
Q

Outline the mechanism of fulvestrant action

A
  1. Fluvestrant binds to oestrogen receptor (ER)

2. this time instead of translocating to the DNA and altering transcription binding causes ER degradation.

37
Q

How does Tamoxifen work?

A

=>Tamoxifen

  • partial agonist but does not cause activation of ER.
  • It has a mixed activity - it activates ER in the uterus and liver but acts as an antagonist in breast tissue.
  • Tomoxifen is a selective estrogen receptor modulator (SERM)
  • when tamoxifen binds to ER it does not fold properly and the AF2 domains do not function.
  • Estradiol binds deep within a pocket in the receptor and is covered by a loop of protein chain, the loop forms part of the activation signal that will stimulate growth in the cell (AF2).
  • Tamoxifen binds, the extra tail of drug is too bulky and receptor loop is not able to adopt its active conformation.
38
Q

Outline the mechanism of tamoxifen

A
  1. tamoxifen binds to ER and makes it partially active(conformational change causes only 1 domain to be active; only AF1 active, AF2 inactive)
  2. partial coactivators recruited
  3. partially inactivated transcription
39
Q

how do aromatase inhibitors decrease oestrogen levels?

A
  • when ovaries are no longer functional in post menopausal women, potential sources of estrogen come from peripheral conversion of androgens by aromatase enzyme.
  • aromatase is present in multiple organs including adipose tissue, brain, blood vessels, skin, bone , endometrium and breast tissue.
  • androgens are hormones such as testosterone, or adrenal androgens such as androstenedione
40
Q

chemical structure changes by aromatase

A
  • conversion of ketone group to OH

- conversion of ketone to an aromatic ring with an alcohol

41
Q

What are 2 types of aromatase inhibitors?

A
  1. type 1 inhibitor : androgen analogues which bind irreversibly to aromatase, so they are also called “suicide inhibitors”. The duration of inhibitory effect is primarily dependent on the rate of novo synthesis of aromatase.
  2. type 2 inhibitors:
    -contain functional group within the ring structure that binds the heme iron to the cytochrome structure
    of the cytochrome P450, interfering with hydroxylation reaction.
42
Q

What is the role of prostate gland?

A

produce semen when mixed with the sperm produced by the testes

43
Q

What type of gland is prostate gland?

A
  • specialised type of exocrine gland called apocrine gland

- exocrine glands secrete substances out onto surface or cavity, via ductal structures.

44
Q

what are 2 developmental phases of normal prostate?

A
  1. hormone independent
    - enlargement during puberty
  2. hormone dependent
    - reactivation of prostate growth in old age - leading to hyperplasia and prostate cancer.
45
Q

What are other abnormalities of prostate?

A
  1. inflammation, eg: due to infection
    - prostatitis - linked to infertility
  2. dysregulated growth of prostate
    - benign: prostatic hyperplasia
    - Malignant: prostate cancer
46
Q

What are symptoms of prostate cancer?

A
  • frequent urination
  • poor urinary stream
  • urgent need to urinate
  • hesitancy whilst urinating
  • lower back pain
  • blood in urine (rare)
47
Q

Where do prostate cancer start?

A
  1. initiation
    - originate in cells that line the lumen in prostate epithelium
  2. progression:
    - prostatic intraepithelial neoplasia (PIN)
  3. Advancement:
    - invasive adenocarcinoma
48
Q

What 3 main ways to detect prostate cancer?

A
  1. digital examination (DRE)
  2. PSA test -Ab based assay
  3. ultrasound
49
Q

Prostate cancer staging

A 
T1: small, localised tumour 
T2: palpable tumour 
T3= grows outside the prostate 
TNM= 
T= stands for the size of the primary tumour (main tumour).
N= number of lymph nodes
-N0 to N3 
M= metastasised or not
M1a = non regional lymph node, M1b = bone, M1c = other  sites.
50
Q

What is the Gleason’s grading system?

A
  1. helps evaluate the prognosis using biopsy samples
  2. samples examined by clinical histologist
  3. prostate cancer staging predicts prognosis and helps guide therapy
  4. cancers with higher Gleasin score are more aggressive and have worse prognosis
51
Q

What are treatment options?

A
  1. watchful waiting = low grade tumour, older patients
  2. radical prostectomy = stage T1 to T2 (confines to prostate gland)
  3. Radical radiotherapy = external upto T3, internal implants
  4. hormone therapy = +/- prostatectomy or radical therapy, metastatic prostate cancer.
52
Q

What are current therapies for prostate cancer?

A
  1. watchful weighting
    - recommended for older men
    - unlikely cancer will affect their natural lifespan.
  2. active surveillance
    - aims to avoid unnecessary treatment of harmless cancers while still providing timely treatment for men who need it.
    - involves regular PSA
    - tests MRI scans and sometimes biopsies to ensure any signs of progression are found as early as possible.
53
Q

What is the tiger and pussy cat scenario?

A
  • some prostate cancers are fairly harmless (pussy cat)
  • some prostate cancers are deadly (bengal tiger)
  • prostate cancer is highly variable and it is unknown what makes some prostate cancers grow very aggressively and others remain slow growing.
54
Q

What are risk factors of prostate cancer?

A
  • age: rare in young men
  • race: African - American more common , less in asian
    -geography : more common in America, Europe, Australia and Caribbean islands.
    -family history: BRCA1 increase risk
    -Diet: dairy products higher chance
  • obesity
  • chemical exposure
  • STDs
    => gene mutations: BRAC1 and PTen loss, point mutation and change in RNAse
55
Q

How does loss of PTEN cause cancer?

A
  • PTEN is a phosphatase that antagonises the phosphatidylinositol 3-kinase signalling pathway.
  • As PTEN is the only known 3’ phosphatase counteracting the PI3/AKT pathway.
  • Loss of PTen results in increased growth factor signalling.
56
Q

TMRS2-ERG

A
  • TMPRS2-ERG fusion gene is the most frequent, present in 40% -80% of prostate cancers.
  • promoter fuses with oncogene ERG strong proliferation driven by testosterone.
57
Q

mechanism of androgen receptor signalling

A
  • AR located in the cytoplasm associated with many cheperone proteins.
  • Testosterone is converted to a more potent agonist (DHT) by 5 alpha-reductase as it crosses into the prostate , DHT then binds to AR with high affinity
  • The DHT-AR dimerised and translocate to the nucleus where it binds to androgen response elements.
  • target gene transcription altered leading to cell growth.
58
Q

Targeting AR in prostate gland

A
  • prostate gland is an androgen sensitive and dependent tissue
  • prostate cancer cells retain this sensitivity and dependency - androgens are a driver of prostate cancer growth
  • Therefore, this can be used as an inherent vulnerability that can be exploited for treatment.
  • switch off AR signalling, switch off the cancer growth
59
Q

What are steps that lead to cell growth and tumour in androgens?

A
  1. cholestrol makes androgenic precursors which circulate in blood
  2. testosterone : cholestrol reach testis and get converted to testosterone.
  3. DHT: testosterone circulates the blood and when it reaches to prostate converted to DHT
  4. AR binding : to DHT in cytoplasm of prostate causes
  5. AR translocation into nucleus
  6. AR DNA binding
  7. AR co-factor recruitment
  8. AR gene transactivation
  9. cell/tumour growth
60
Q

What inhibits testosterone synthesis?

A

=> Abiraterone acetate inhibits cholesterol -> androgen
=> antagonists of GnRH can inhibit LH and FSH release so less bind to testis so less testosterone released.
=> examples synthetic GnRH :
Goserlin -agonist
Abrexlin - antagonist

61
Q

What inhibits testosterone to DHT?

A

5-alpha reductase inhibitor

commonly used for benign prostate hyperplasia

62
Q

What inhibits DHT -> AR binding?

A
  • competitive inhibitors of androgen binding to the receptor.
  • Eg:
  • Bicalutamide
  • enzalutamide
  • flutamide
  • nilutamide
63
Q

What happens in the presence of agonist and androgen antagonist?

A
  1. unliganded
    - >inactive transcription factor
    - > open inliganded receptor
  2. correct ligand binding
    - >correct ligand binding AR Helix folds over creating active transcription factor
  3. incorrect ligand binding
    - > AR helix 12 cannot fold over creating inactive transcription factor.
64
Q

Why is hormone therapy not effective over time?

A
  • begin to fail over time and patient relapse with hormone refractory cancer
  • homogenous cancer cells develop various mechanisms to overcome hormonal starvation
65
Q

What are different mechanisms to lower hormone levels?

A
  1. some breast and prostate advanced tumour start to synthesis their own steroid hormones
  2. ligand binding site mutations make receptor promiscuous
  3. signal amplification and increased sensitivity to low hormone levels
  4. cross over with other signal pathways, eg: growth factors can phosphorylate and activate receptors prevalent for breast cancers.
  5. androgen receptor transcript variants: activation in absence of ligand
  6. possible switch to other transcription factors or oncogenes
  7. receptor cofactor amplification can amplify the signal from steroid receptors in response to a low level of steroid hormone.
  8. Antagonists used for prostate cancer treatment can become potent activators of a mutant androgen receptor.
66
Q

What are the two DNA binding domain structures?

A

Zinc fingers domains

  1. CI zinc finger
    - specific DNA sequence binding
  2. CII zinc finger
    - interaction with the DNA phosphate backbone
67
Q

What are hormone response elements?

A
  • specific DNA sequences found in the promoters of hormones responsive genes, many are palindromic.
  • 12 DNA bases separated into 6 and 6 by spacers.
  • estrogen and glucocorticoid

molecular basis of disease (29 decks)

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