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Molecular Basis of Disease - SGUL (Sem 4) > Introduction to Hormone Dependent Cancers - Breast and Prostate Cancer > Flashcards

Introduction to Hormone Dependent Cancers - Breast and Prostate Cancer Flashcards

1
Q

What is a hormone

A

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.

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2
Q

List some places where hormones are produced

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

What are the three classes of hormones

A
  • Steroid/lipids - testosterone
  • Peptide/proteins - insulin
  • Amino acids - adrenaline
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4
Q

What are steroid hormones

A
  • Hormones derived and synthesised from cholesterol
  • Converted in the adrenal cortex
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5
Q

Describe how steroid hormones are synthesied

A
  • Cholesterol is converted into hormones in the adrenal cortex
  • androgens and oestrogens are produced in target tissues then released into the blood stream
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6
Q

Give some examples of steroid hormones

A
  • Androgen: testosterone
  • Estrogen: Estradiol
  • Progestogen: progesterone
  • Corticosteroid: cortisol
  • Mineralocorticoid: aldosterone
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7
Q

Why do we study sex hormones

A
  • they are responsible for sexual dimorphism between males and females
  • The development of secondary sexual characteristics
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8
Q

what effects do steroid hormones have in females

A

In females oestrogen controls the menstrual cycle, and breast tissue development, fertility, and reproductive organ development, secondary sexual characteristics - body hair etc.

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9
Q

what effects do steroid hormones have in males

A

In males testosterone controls reproductive and supportive organs (prostate), development of sexual characteristics in men e.g. deepening of the voice, body hair etc

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10
Q

How do hormones govern cancer growth and treatment

A
  • When cancers arise in breast or prostate tissues –
    the steroid hormones can still influence how the cells grow and function, and consequently how the
    the disease develops and progresses
  • The dependence of these tissues on steroids can be exploited when it comes to treatment of these cancers
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11
Q

Describe how steroid hormones elicit a response I cells

A
  • They enter the cells and bind to their receptors
  • Their receptors are nuclear receptors and have their effects in the nucleus.
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12
Q

Describe the nuclear receptor mechanism when binding steroid hormones

A
  1. Steroid hormones cross into the cell cytoplasm where they will bind to their receptor
  2. Binding to the receptor causes a conformational change in the nuclear receptor, causing it to become activated (some nuclear receptors dimerise at this point)
  3. Nuclear receptors then translocate into the nucleus
  4. Nuclear receptors bind to specific DNA sequences called response elements located in the promoters of steroid-responsive genes.
  5. Steroid responsive genes are switched on and upregulated.
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13
Q

What are the three basic domains of a nuclear receptor

A
  • Ligand binding domain: binds specific steroid molecules with high affinity
  • DNA binding domain: Binds specific DNA sequence
  • Activation function domain: Recruits gene activation machinery, some receptors have a secondary AF2 domain towards the C-terminal
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14
Q

How is the nuclear receptor activated

A
  • They get activated when they bind steroid hormones thus called ligand-activated receptors
  • Binding of ligand causes a conformational change and physical restructuring of the polypeptide chain in the receptors
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15
Q

Describe the ligand activated transcription factor sequence

A
  • Ligand binds to binding site in and alpha helix activating the receptor
  • the receptor dimerises and moves into the nucleus and binds to specific DNA sequences
  • The receptor then recruits DNA modifying enzymes, transcription factors and RNA polymerases to promoters of hormone responsive genes
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16
Q

How does the zinc-finger domains present in the receptor help in DNA binding

A
  • The zinc group holds the amino acid chain rigidly, allowing specific sequence binding.
  • Helps with the interaction with DNA phosphate backbone
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17
Q

What is a Hormone Response Element

A

Specific DNA sequences found in promoters of hormone responsive genes.

Many are palindromic

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18
Q

List the main steroid receptors

A
  • Estrogen receptor: ER
  • Androgen receptor: AR
  • Progesterone receptor: PR
  • Glucocorticoid receptor: GR
  • Mineralocorticoid receptor: MR
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19
Q

What is the normal function of the breast

A
  • An apocrine gland that produces milk
  • Composed of glands and ducts which produce the fatty breast milk
  • The milk producing part of the breast is organised into 15 to 20 sections called lobes
  • Each lobe consists of smaller structures called lobules where milk is produced
  • Milk travels through tiny tubes called ducts and come together to form a bigger duct and terminate at the nipple
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20
Q

What is an apocrine gland

A

Specialised exocrine gland in which part of the cells’ cytoplasm breaks off releasing the contents

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21
Q

Describe the tissue structure of the mammary gland

A

Consists of two cell compartments:

  • Luminal: single layer of polarised epithelium around the ductal lumen, luminal cells produce milk during lactation
  • Basal: cells that don’t touch the lumen, basally orientated myoepithelial cells in contact with the basement membrane, contractile function during lactation
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22
Q

What are the 2 phases in breast development

A
  • hormone-independent from embryonic development up to puberty
  • hormone-dependent thereafter during puberty, menstrual cycle and
    pregnancy.
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23
Q

What is the function of the oestrogen receptor in normal breasts

A
  • Drives the expression of genes involved in cellular proliferation and differentiation
  • Hormone-dependant mammary gland development occurs after puberty and results in ductal elongation and triggers side branching
  • Adult oestrogen 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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24
Q

Describe progesterone activity in the normal breasts

A
  • Estrogen is primarily involved in the initial growth of breast cancer
  • The progesterone receptor gene is switched on by the estrogen 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).
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25
Q

What are the risk factors involved in cancer development

A
  • Age
  • Lifestyle
  • Genetic familial factors
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26
Q

List some causes of breast cancer

A
  • Age
  • Genetic mutations to certain genes e.g: BRCA1, BRCA2
  • Reproductive history: early onset of menstrual cycle before 12yrs and start to menopause after 55yrs
  • Previous treatments using radiation therapy
  • Low physical activity
  • Obesity
  • Taking hormones
  • Alcohol
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27
Q

What are the characteristics of Ductal breast carcinoma in situ

A
  • Breasts are made of lobules and ducts which are surrounded by glandular, fibrous and fatty tissue
  • When cancer develops within the ducts and remains in the ducts it is called DCIS.
  • It hasn’t reached the ability to spread outside these ducts into surrounding breast tissue.
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28
Q

What are the characteristics of Lobular breast carcinoma in situ

A
  • Uncommon condition where abnormal cells form in the milk glands
  • LCIS isn’t cancer, but its diagnosis indicates an increased risk of developing cancer
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29
Q

Where and where not are oestrogen receptors expressed

A
  • Epithelial cells express ER and the majority of breast cancers arise from luminal cells
  • Myoepithelial cells down express ER
30
Q

What is the difference between ER+ve and ER-ve breast cancer

A
  • The majority of breast cancers are ER +ve 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.
31
Q

How do changes in the oestrogen receptor cause breast cancer

A
  • Normally ER controls functions such as cell proliferation, development and differentiation in a tightly controlled manner
  • In breast cancer, 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 RNA’s and miRNAs
  • ER then governs cancer cell proliferation and control genes involved in metastasis, invasion and adhesion
32
Q

How can we target ER in breast cancer

A
  • The mammary gland is an estrogen sensitive and dependent tissue
  • Breast cancer cells retain this sensitivity and dependency –
    estrogens are a key driver of breast cancer growth.
  • Therefore, this can be used as an inherent vulnerability that can be
    exploited for treatment.
  • Switch off ER signalling, switch off the cancer growth
33
Q

How can we inhibit oestrogen activity

A
  • Pharmaceutically competitively blocking oestrogen receptors binding and degrading ER protein
34
Q

How does Fulvestrant (Faslodex) work to treat breast cancer

A
  • Fulvestrant is an analogue of
    estradiol.
  • Fulvestrant competitively inhibits the 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.
  • The drug-receptor complex is unstable resulting in an accelerated degradation of ER protein
35
Q

How does Tamoxifen work to treat breast cancer

A
  • 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
36
Q

How does tamoxifen binding differ at the ER receptor

A
  • Estradiol binds deep within a pocket in the receptor
  • The loop forms part of the activation signal that will stimulate growth in the cell
  • Tamoxifen binds the extra tail of the drug is too big for the receptor and the loop is not able to adopt its active conformation
37
Q

What are aromatase inhibitors and how do they work

A
  • The enzyme converts androgens into oestrogens and the enzyme is present all around the body
  • When the enzyme is inhibited the production of estrogens are decreased
38
Q

What are the types of aromatase inhibitors

A

Type 1:

  • Androgen analogues that bind irreversibly to aromatase so are called suicide inhibitors. e.g: Exemestane

Type 2:

  • Contains a functional group with a ring structure that binds the heme iron of cytochrome p450 interfering with hydroxylation reactions. e.g: anastrazole
39
Q

Why are we interested in studying prostate cancer

A
  • Prostate cancer is rapidly becoming the most common cancer in males in the UK
  • Rising incidence rates, 48,500 new prostate cancer cases in the UK every year
40
Q

What is the normal function of the prostate galnd

A

Produce prostatic fluid that creates semen when mixed with sperm produced in the testes.

Apocrine gland

41
Q

Describe the development of the normal prostate

A

Prostate gland development can be separated into phases:

  • hormone-independent from embryonic development up to puberty
  • enlargement during puberty
  • hormone-dependent maintenance thereafter in adulthood

And – reactivation of prostate growth in old age – leading to
hyperplasia and prostate cancer

42
Q

List some prostate abnormalities

A

Inflammation due to infection:

  • Prostatitis - linked to infertility

Dysregulated growth of prostate:

  • Benign - benign prostatic hyperplasia
  • Malignant - Prostate cancer
43
Q

List some symptoms related to prostate cancer

A
  • frequent trips to urinate
  • poor urinary stream
  • an urgent need to urinate
  • hesitancy whilst urinating
  • lower back pain
  • blood in the urine (rare)
44
Q

Where does prostate cancer start

A
  • Initiation: Luminal cells begin to proliferate uncontrollably
  • Progression: There is a large number of luminal cells in the basement membrane
  • Advancement: The neoplastic cells break away and metastasise
45
Q

How can we detect prostate cancer

A
  • Digital rectal examination
  • PSA test: Blood sample antibody-based assay
  • Ultrasound: Detect tumour outside prostate capsule
46
Q

How is prostate cancer progression stages with the TNM grading system

A
  • T1: small, localised
  • T2: Palpable tumour
  • T3: Escape from prostate gland
  • T4: Local spread to pelvic region
47
Q

What does the N classify in the TNM grading system

A

Tumour in Lymph node:

  • N0: No cancer in lymph node
  • N1: 1 positive lymph node <2cm across
  • N2: more than 1 positive lymph node or 2-5 cm across
  • N3: Any positive lymph node >5cm across
48
Q

What does the M classify in the TNM grading system

A

Has the tumour metastasised:

  • M1a: Non-regional lymph nodes
  • M1b: Bone
  • M1c: other sites
49
Q

What is the Gleason’s grading system for prostate cancer

A

Used to evaluate prognosis of men using prostate biopsy samples

  • Small, uniform glands
  • More stroma beween glands
  • Distinctly infiltrative margins
  • Irregular masses of neoplastic glands
  • Only occasional gland formation
50
Q

How can we treat prostate cancer

A
  • Watchful waiting: low-grade tumour, elderly
  • Radical prostatectomy: Stage T1 or T2
  • radical radiotherapy: External up to T3, internal impacts for T1/2
  • Hormone therapy: Metastatic prostate cancer
51
Q

What is the tigers and pussycats scenario

A

A lot of men with prostate cancer are never treated but watched and yet many men die from it.

  • Prostate cancer is highly variable: in some men, it is fairly harmless like pussy cats and in some, it can be deadly like tigers.
52
Q

What are the risk factors for prostate cancer

A
  • Age
  • Race/ethnicity
  • Geography
  • Family history
  • Gene changes/inherited
  • Other risk factors: diet, obesity, chemical exposure, STI and prostatitis
53
Q

What are some gene mutations associated with prostate cancer

A
  • Pten
  • TMPRSS2-ERG fusion
  • BCRA1
54
Q

How does Pten mutation cause prostate cancer

A
  • Pten is a phosphatase that antagonises the phosphatidylinositol 3-kinase signalling pathway
  • It is the only knows 3’ phosphatase counteracting the PI3K/AKT pathway
  • Loss of Pten results in increased growth factor signalling
55
Q

Describe how the TMPRSS2-ERG fusion results in prostate cancer

A
  • TMPRSS2-ERG fusion gene is the most frequent, present in 40% - 80% of prostate cancers in humans
  • AR now drives proto-oncogene ERG which leads to inappropriate gene activation
56
Q

How does androgen signalling occur

A
  • Testosterone is converted to a more potent agonist called DHT as it enters the prostate.
  • DHT binds androgen receptors: Ligand binding
  • Dimerisation
  • DNA binding
  • Coactivator recruitment
  • Target gene converted to target protein leading to cell growth
57
Q

How can we target AR in prostate cancer

A
  • The prostate gland is an androgen sensitive and dependent tissue
  • Prostate cancer cells retain this sensitivity and dependency – androgens are a key 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 the cancer
58
Q

How can we inhibit testosterone synthesis

A
  • The adrenal gland derived androgens circulate in the blood, and are finally converted to testosterone in the testes.
  • Testosterone then circulates in the blood where it reaches end target organs e.g. prostate
  • The adrenal androgen production can be inhibited, thus depriving the testes of testosterone
59
Q

Describe how Abiraterone acetate works to reduce testosterone synthesis

A
  • Stops the congestion from cholesterol into adrenal androgen intermediates
  • Reduction of adrenal androgen precursors leads to reduction in testosterone
60
Q

How can we inhibit hormone synthesis that causes testosterone synthesis

A

GnRH (gonadotropin-releasing hormone) triggers the production of testosterone in the testes

  • Goserelin – super agonist
  • Abarelix – antagonist

Overall the actions of superagonists and antagonists are similar – they depress testosterone production in the testes

61
Q

How can we block the conversion of testosterone into DHT

A

Finasteride blocks the 5-alpha reductase enzyme from converting testosterone into DHT

62
Q

How can we inhibit androgens from binding to its receptor

A

Use competitive anti-androgens/ androgen blockers to stop DHT from binding its receptor

  • Bicalutamide
  • Enzalutamide
  • Flutamide
  • Nilutamide
63
Q

How does hormone overproduction reduce hormone therapy effectiveness

A

Some breast and prostate advanced tumours start to synthesise their steroid hormones which stimulate their own receptors

64
Q

How do ligand binding site mutations reduce hormone therapy effectiveness

A
  • Ligand binding site mutations make receptors promiscuous
  • Other proteins can bind and elicit a response
65
Q

How does receptor amplification reduce hormone therapy effectiveness

A

Signal amplification and increased sensitivity to low hormone levels

66
Q

How does receptor phosphorylation reduce hormone therapy effectiveness

A

Cross over with other signal pathways can phosphorylate and activate receptors
- Prevalent for breast cancers

67
Q

How does Androgen receptor transcript variants reduce hormone therapy effectiveness

A

Androgen receptor variants that are truncated and are without a c terminus can be active without a ligand present

68
Q

How does receptor bypass reduce hormone therapy effectiveness

A

Possible switch to other transcription factors or oncogenes

69
Q

How does receptor cofactor amplifacation reduce hormone therapy effectiveness

A

Cofactor amplification can amplify the signal from steroid receptors in response to a low level of steroid hormones

70
Q

How does antagonists becoming agonists via LBD mutations reduce hormone therapy effectiveness

A

Antagonists used for prostate cancer treatment can become potent activators of a mutant androgen receptor

Molecular Basis of Disease - SGUL (Sem 4) (29 decks)

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