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mbd > Introduction To Hormone Dependant Cancers: Breast And Prostate Cancers > Flashcards

Introduction To Hormone Dependant Cancers: Breast And Prostate Cancers Flashcards

1
Q

What is a hormone?

A

Chemical messenger made by specialist cells and is released into the bloodstream to have an effect in another part of the body

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2
Q

Where are hormones produced?

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

What are the three groups of hormones?

A
  • Steroids
  • Peptide/proteins
  • Modified amino acids/amine hormones
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4
Q

What are steroids synthesised from?

A

Cholesterol

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5
Q

Which tissue in the adrenal glands are steroid synthesised?

A

In the adrenal cortex

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6
Q

Name 5 different classes of steroids

A
  • androgen (testosterone)
  • estrogen (estradiol)
  • progestogen (progesterone)
  • corticosteroids (cortisol)
  • mineralocorticoids (aldosterone)
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7
Q

Name the 2 most prevalent cancers in the UK

A
  • breast
  • prostate

Both tissues are heavily influenced by steroid hormones - these tissues are hormone dependant. So the cancer can also be dependant on hormones.

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8
Q

What are steroid response elements - describe their structure?

A

Specific sequences in the DNA on promoters where the steroid-receptor complex binds to. So the steroid + receptor complex acts as a TF.

  • many are palindromic repeats
  • hormone response elements for estrogen are called estrogen response elements etc.
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9
Q

Name the 3 domains in all steroid nuclear receptors

A
  • LBD - ligand binding domain
  • DBD - DNA binding domain
  • AF1 and AF2 - activation function domain
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10
Q

What is the function of the AF1 domain?

A

Activation function domains -

Recruits gene activation machinery, some receptors have AF2 further towards the C terminal

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11
Q

Describe the general mechanism of steroid receptors

A
  • This is after the ligand binds to LBD that changes its structure to activate it.
  • Also, some of the receptors will dimerise.
  • Hormone responsive genes can be downregulated or upregulted and many hundreds of genes can be regulated by a steroid receptor
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12
Q

What are sex hormones responsible for?

A

Sexual dimorphism between males and females and development of secondary sexual characteristics

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13
Q

What are the effects of female sex steroid hormones?

A

Oestrogen controls the menstrual cycle and breast tissue development, fertility and reproductive organ development

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14
Q

What are the effects of male sex steroid hormones?

A

Testosterone controls reproductive and supportive organs (prostate) and development of secondary characteristics

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15
Q

Why are breast/prostate cancer the most commonly diagnosed?

A
  • Tissues are hormone dependant
  • Steroids control several aspects of cellular proliferation, tissue function, gene expression and morphology
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16
Q

What is the steroid mechanism of action?

A
  • Enters cell and binds to cytoplasmic receptor
    → Conformational change in the receptor (causing it to become activated) → dissociated from the cytoplasmic proteins and translocates into the nucleus
    → receptor binds to DNA promoter regions and act as transcription factors and induces gene expression
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17
Q

What are the key characteristics of a nuclear receptor?

A
  • Ligand binding domain
  • DNA binding domain
  • Activation function domain
  • Ligand activated
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18
Q

What does the ligand binding domain of a nuclear receptor do?

A

Binds specific steroids with a high affinity

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19
Q

What does the DNA binding domain of a nuclear receptor do?

A

Binds specific DNA sequences

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20
Q

What does the activation function domain of a nuclear receptor do?

A

Recruits gene activation machinery, some receptors have a secondary af2 domain towards the c-terminal

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21
Q

What does ligand binding to the ligand binding site cause?

A

A shift in the alpha helix, which activates the receptor

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22
Q

How are hormone responsive genes controlled?

A

Up or down regulated by steroid hormones

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23
Q

What are hormone response elements?

A

Specific DNA segments found in the promoters of hormone response genes

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24
Q

What are hormone response elements made up of?

A

6 bases, 3 spacer DNA bases, 6 bases

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25
Q

How many genes are contained in the nuclear receptor superfamily?

A

48

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26
Q

What do the nuclear receptor superfamily share?

A

Common domain receptor structure

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27
Q

What does the main steroid receptor depend on?

A

The thing they bind

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28
Q

What is a zinc finger domain?

A

Zinc finger, binds to hormone response elements:

  • CI Zinc finger
  • CII Zinc finger
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29
Q

Describe the function of CI Zinc finger?

A

specific DNA sequence binding

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30
Q

Describe the function of CII Zinc finger

A

interaction with the DNA phosphate backbone

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31
Q

What is the breast?

A

Breast is an apocrine gland that produces milk

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32
Q

What is the mammary gland tissue composed of?

A

Glands and ducts that produce fatty breast milk

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33
Q

What is the type of the gland that produces milk?

A

Apocrine gland

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34
Q

What is the milk producing part of the breast organised into (and what are they called)?

A
  • 15-20 sections called lobes
  • within each lobe is lobules, where milk is produced
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35
Q

What does milk travel through in the breast?

A

Networks of tiny tubules called ducts

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36
Q

What does an exocrine gland do?

A

Secretes substances out onto a surface or cavity via a ductal structure

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37
Q

What does an endocrine gland do?

A

Secrete substances directly into the bloodstream

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38
Q

What is an apocrine gland?

A

Specialised exocrine gland in which a part of the cell’s cytoplasm breaks off, releasing the contents

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39
Q

Describe the 2 cell types in the mammary gland

A
  • Luminal
  • Basal
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40
Q

What is the function of the luminal cells in the mammary gland?

A

Luminal cells form a single layer of polarised epithelium and the ductal lumen

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41
Q

What do luminal cells produce (And when?)

A

Milk during lactation

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42
Q

What is the basal mammary gland tissue structure?

A

Comprise the cells that do not touch the lumen and basally orient the epithelial cells in contact with the basement membrane

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43
Q

What are the two major phases in mammary gland development and when do they happen?

A
  • Hormone independant (embryonic → puberty)
  • Hormone dependant (after puberty)
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44
Q

What does hormone dependant mammary gland development cause?

A

Ductal elongation and side branching

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45
Q

In an adult what does estrogen allow for in the breast?

A

Maintenance of mammary gland tissue and primes it for the effects of progesterone during pregnancy for milk production

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46
Q

Describe the differing effects of oestrogen, progesterone and prolactin on the ducts in the mammary glands (think about their roles in the endometrium)

A
  • Oestrogen causes ductal elongation (so mostly growth?)
  • Progesterone causes ductal elongation and side branching (differentiation?)
  • Prolactin causes alveogenesis and lactogenic differentiation
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47
Q

What is the aetiology of breast cancer (not including normal cancer ones)?

A
  • genetic mutations such as BRCA1 and BRCA2
  • reproductive history (early onset of menstrual cycle before 12 years and starting menopause after 55 years means that women are exposed to hormones for longer)
  • previous radiotherapy to the chest
  • taking hormones including certain oral contraceptives
  • first pregnancy after 30,
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48
Q

What facets of the reproductive history increase the chance of breast cancer?

A
  • Early menstrual cycle onset (before 12)
  • Menopause after 55
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49
Q

What is meant by DCIS?

A

DCIS = ductal carcinoma in situ

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50
Q

What causes a ductal breast carcinoma in situ (DCIS)?

A
  • This is when cancer cells develop in the ducts and remain in the ducts
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51
Q

Why do the cancer cells not spread more in DCIS?

A

Not yet developed the ability to spread

52
Q

What is meant by LCIS?

A

Lobular carcinoma in situ - when the abnormal cells are in the milk glands (lobules)

53
Q

Is lobular breast carcinoma in situ cancer?

A

No but indicates there could be an increased risk of its development

54
Q

Which tissue of the breast does most cancer arise from and what receptor do they express?

A

Luminal cells, expressing ER (oestrogen receptor)

55
Q

What is the prognosis for estrogen and progesterone receptor positive cancers?

A

Good

56
Q

What is the prognosis for estrogen and progesterone receptor negative cancers?

A

Poor

57
Q

Describe the role of the ER receptor in breast cancer

A
  • ER’s ability to bind to DNA and open chromatin becomes hijacked and is used to transcribe many genes, non-coding RNAs and miRNAs
  • ER then governs many genes involved in cell proliferation, metastasis, invasion and adhesion
  • Breast cancer cells retain the mammary gland dependency on oestrogen so we can block ER receptor in treatment
58
Q

Describe in detail how oestrogen exerts its effects in a cell

A
  • Goes across membrane, binds to LBD, receptor dimerises
  • receptor dimer binds to DNA at specific sites, AF1 and AF2 activated
  • → so many coactivators are recruited to regulate gene expression of certain genes
59
Q

How are estrogen and progesterone receptor negative cancers treated?

A

Hormonally

60
Q

What happens when the estrogen receptor pathway is subverted?

A

ER’s ability to bind DNA and open chromatin is hijacked and used to transcribe many genes and RNAs

It then governs cancer cell proliferation

61
Q

What is fulvestrant?

A

Analogue of estradiol

62
Q

How does fulvestrant work?

A

Competitively inhibits binding of estradiol to the ER, with a binding affinity that is 89% that of estradiol

63
Q

What does the fulvestrant- ER complex do?

A

Impairs receptor dimerisation and energy dependant nucleo-cytoplasmic shuttling. This blocks nuclear localisation of the receptor

64
Q

How does tamoxifen work?

A

Binds to the ER at the ligand binding site

65
Q

Is tamoxifen an agonist or an antagonist?

A

Agonist in uterus but antagonist in breast tissue

66
Q

What happens to tamoxifen bound ER?

A

Doesnt fold properly and AF2 domains do not function,

67
Q

Where does estradiol normally bind to the ER?

A

Deep within a pocket in the receptor

68
Q

What happens when estradiol binds to ER?

A

Covered by a loop of protein chain, which is its active configuration

69
Q

How does tamoxifen affect the binding of estradiol to the ER?

A

Binds to the chain that covers bound estradiol causing it to be too bulky to cover it, so it cant adopt its active conformation

70
Q

Where does estrogen come from in post-menopausal women?

A

Peripheral conversion of androgens by blood vessels

71
Q

Where is the aromatase enzyme present?

A

Adipose tissue, brain, blood vessels, skin, bone, endometrium and breast tissue

72
Q

What is a type 1 aromatase inhibitor?

A

androgen analogues and bind irreversibly to aromatase

73
Q

What is an example of a type 1 aromatase inhibitor?

A

Exemestone

74
Q

What is the duration of type 1 aromatase inhibitor effect dependant on?

A

Rate of de novo aromatase synthesis

75
Q

What is an example of a type 2 aromatase inhibitor?

A

Mastozole

76
Q

What do type 2 aromatase inhibitors contain?

A

Functional group within the ring structure that binds to the haem iron of cytochrome P450, interfering with hydroxylation reactions

77
Q

What is the main function of normal prostate gland tissue?

A

Produces prostatic fluid to add to the semen when mixed with other secretions and sperm

78
Q

What type of gland is a prostate gland?

A

Exocrine (apocrine)

79
Q

What are the 3 main types of cells found in the prostate?

A
  • luminal epithelial cells
  • basal epithelial cells
  • stromal smooth muscle cells
80
Q

What are the steps in prostate development?

A
  • Hormone independant (embryo → puberty)
    • Englargement during puberty
  • Hormone dependant maintenance in adulthood
  • Reactivation of prostate growth in old age
81
Q

What is prostatitis?

A
  • abnormalities of the prostate
  • Prostate inflammation due to infection - can cause infertility
82
Q

Describe what BPH is

A
  • Abnormality of the prostate
  • BPH is benign prostatic hyperplasia which is the benign dysregulated growth of the prostate
83
Q

What are the two types of dysregulated prostate growth?

A
  • Benign - benign prostatic hyperplasia
  • Malignant - prostate cancer
84
Q

What are the symptoms of prostate cancer?

A
  • Frequent urination
  • Poor urinary stream
  • Urgent need to urinate
  • Hesitancy while urinating
  • Lower back pain
  • Blood in urine
85
Q

Which cell type does prostate cancer usually start in?

A

In the luminal epithelium (like in breast cancer)

86
Q

What is meant by prostatic intarepithelial neoplasia vs invasive adenocarcinoma?

A

Prostatic intraepithelial neoplasia is what happens first before becoming an invasive adenocarcinoma when there is cancer of the luminal epithelium of the prostate

87
Q

What does hyperproliferation of the luminal epithelium cause?

A

Prostate intraepithelial neoplasia

88
Q

How can prostate cancer be detected?

A
  • Digital rectal examination
  • PSA test (prostate antigen blood test)
  • Ultrasound
89
Q

What is meant by the TNM staging of cancer?

A
  • T is the size
  • N is if spread to the lymph nodes involved
  • M is if it has metastasised
90
Q

What are the classes of prostate cancer?

A
  • T (1-4)
  • N (0-3)
  • M (1a-c)
91
Q

What is a T1 tumour?

A

Small localised tumour

92
Q

What is a T2 tumour?

A

Palpable tumour

93
Q

What is a T3 tumour?

A

Escape from prostate gland

94
Q

What is a T4 tumour?

A

Local spread to pelvic region

95
Q

Explain the grading of a biopsy staining by Gleason’s grading system

A
  • Grades the sample based on how poorly differentiated the tissue is as a cancerous tissue will be very undifferentiated in comparison to the healthy tissue as seen in the image above.
  • Higher Gleason score means the cancer is more aggressive and has a worse prognosis.
96
Q

What is a N0 tumour?

A

No cancer in any lymph nodes

97
Q

What is a N1 tumour?

A

One positive lymph node <2cm big

98
Q

What is a N2 tumour?

A

more than 1 positive lymph node or one 2-5 cm big

99
Q

What is a N3 tumour?

A

Any positive lymph node >5cm across

100
Q

What is a M1a tumour?

A

Non-regional lymph nodes

101
Q

What is a M1b tumour?

A

Bone

102
Q

What is a M1c tumour?

A

Other sites

103
Q

What are the stages in the gleason grading system?

A
  1. small, uniform glands
  2. more stroma between glands
  3. distinctly infiltrative margins
  4. irregular masses of neoplastic glands
  5. only occasional gland formation
104
Q

Name some treatment options for different prostate cancer stages

A
  • ‘Watchful waiting’ for low grade tumour in older patients
  • Radical Prostatectomy for stage T1 or T2 (confined to prostate)
  • Radical Radiotherapy for up to T3
  • Hormone therapy often done alongside surgery or radiotherapy
105
Q

Explain a large difficult with prostate cancers

A

Prostate cancer is highly variable in the sense that in some men it is harmless but in others it can be extremely deadly and it is unknown what makes a cancer very aggressive as opposed to being slow growing

106
Q

Name some risk factors of prostate cancer

A
  • Genetic risk genes (BRCA1 and BRCA2, HNPCC)
  • Age (rare in men younger than 40, rises rapidly after 50)
  • Race or ethnicity (less in asian people and more in black people - could be cultural as well as genetic)
  • Diet, obesity, chemical exposures, inflammation of the prostate, STDs
107
Q

Name the main gene mutations found in prostate cancer

A
  • BRCA1 and PTen loss
  • TMPRSS2-ERG
  • Various other miRNA changes and point mutations
108
Q

Describe what PTen is

A

A phosphatase that antagonises the PIP3 kinase pathway - it is the only known 3’ phosphatase counteracting this pathway

109
Q

What does loss of pten result in?

A

Loss of PTEN causes increased growth factor signalling so causes cell survival and decreased apoptosis

110
Q

Explain what TMPRSS2-ERG is

A

Is the most frequent fusion gene found in prostate cancers (40-80% of all prostate cancers in humans)

  • AR (androgen receptor) will drive the TMPRSS2 gene which has a hormone sensitive promoter
  • When this promoter fuses to ERG (a proto-oncogene) then ERG is upregulated in response to testosterone and becomes an oncogene
111
Q

Describe the role of testosterone with the prostate and prostate cancer

A

Growth and development of the prostate is dependant on androgens including the most common, testosterone - it is androgen dependant for survival

  • androgens are a key driver for prostate cancer growth so we can block AR in treatment
112
Q

Where is the testosterone receptor present in the prostate?

A

Luminal epithelial cells (not basal or stromal)

113
Q

What happens to testosterone when it enters the cell, does it just bind to AR?

A

No, it is first converted into DHT (dihydrotestosterone) by 5-alpha reductase before binding to AR and then dimerising and then binding to ARE (androgen response elements) on DNA

114
Q

Where are androgenic precursors synthesised?

A

Adrenal glands secreted into blood, then converted in the testes to testosterone. The main two are:

  • androsteinone
  • dehydroepiandrosterone
115
Q

Describe how Abiraterone acetate (ZYTIGA) functions

A

Inhibits the synthesis of adrenal androgens (precursors to testosterone) so that testosterone can not be synthesised in the testes

116
Q

Name other ways to stop testosterone signalling in the prostate

A
  • Inhibition of the HPA axis such as synthetic peptides
  • 5 alpha reductase inhibition
  • AR binding competition
117
Q

What are some examples of synthetic peptides?

A
  • Goserelin = super agonist to GnRH
  • Abarelix = antagonist to GnRH
118
Q

What are finasteride and dutasteride?

A

5 alpha reductase inhibitors

119
Q

Describe how Finasteride works

A

Is a 5 alpha reductase inhibitor so less testosterone can become DHT

120
Q

What are some examples of anti-androgens?

A
  • Bicalutamide
  • Enzalutamide
  • Flutamide
  • Nilutamide
121
Q

Describe how Bicalutamide works

A

Competitive antagonist for AR so competes with testosterone for the LBD

122
Q

What are 5 alpha reductase inhibitors commonly used for?

A

Benign prostate hyperplasia

123
Q

What happens to hormone therapies over time?

A

Become less and less effective because cells develop mechanisms to overcome hormonal starvation

124
Q

What kind of mechanisms can tumours develop to overcome hormonal starvation?

A
  • Tumours start to synthesise their own steroid hormones
  • Mutations making ligand binding sites less specific
  • Receptor bypass
  • Receptor cofactor amplification
  • Antagonists become agonists via ligand binding domain mutations
125
Q

What is the ARV7?

A
  • Androgen receptor variant 7
  • Is a variant that is truncated without the C terminus and is active without the ligand in some prostate cancers
126
Q

Explain what receptor cofactor amplification is

A
  • Another mechanism for prostate cancer hormone therapy resistance
  • Is the amplification of cofactors causing the cell to be more sensitive to low levels of the hormone (signal is amplified more)
127
Q

Describe one more mechanism for resistance to hormonal therapies, but this one is specific to prostate cancers

A
  • A mutation in the LBD of the AR (androgen receptor) that causes antagonists to the receptor to become agonists and activate the receptor
  • These therapies would actually drive the disease in this case

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