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Molecular Basis Of Disease/ Microbiology And Immunology > Introduction To Hormone Dependant Cancers: Breast And Prostate Cancers > Flashcards

Introduction To Hormone Dependant Cancers: Breast And Prostate Cancers Flashcards

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Biology 101 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

Where are the main corticosteroids and mineralocorticoids synthesised?

A

In the adrenal cortex

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6
Q

What are sex hormones responsible for?

A

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

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7
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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8
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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9
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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10
Q

What is the steroid mechanism of action?

A

Enters cell and binds to cytoplasmic receptor

  • > Conformational change in the receptor -> 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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11
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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12
Q

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

A

Binds specific steroids with a high affinity

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13
Q

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

A

Binds specific DNA sequences

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14
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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15
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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16
Q

How are hormone responsive genes controlled?

A

Up or down regulated by steroid hormones

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17
Q

What are hormone response elements?

A

Specific DNA segments found in the promoters of hormone response genes

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18
Q

What are hormone response elements made up of?

A

6 bases, 3 spacer DNA bases, 6 bases

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19
Q

How many genes are contained in the nuclear receptor superfamily?

A

48

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20
Q

What do the nuclear receptor superfamily share?

A

Common domain receptor structure

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21
Q

What does the main steroid receptor depend on?

A

The thing they bind

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22
Q

What is the mammary gland tissue composed of?

A

Glands and ducts that produce fatty breast milk

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23
Q

What is the type of the gland that produces milk?

A

Apocrine gland

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24
Q

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

A

15-20 sections called lobes

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25
Q

What does milk travel through in the breast?

A

Networks of tiny tubules called ducts

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26
Q

What does an exocrine gland do?

A

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

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27
Q

What does an endocrine gland do?

A

Secrete substances directly into the bloodstream

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28
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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29
Q

What is the luminal structure of the mammary gland?

A

Form a single layer of polarised epithelium and the ductal lumen

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30
Q

What do luminal cells produce (And when?)

A

Milk during lactation

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31
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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32
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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33
Q

What does hormone dependant mammary gland development cause?

A

Ductal elongation and side branching

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34
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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35
Q

What is the etiology of breast cancer?

A 
Age (normally >50) 
Genetic mutations (BRCA1 and 2)
Reproductive history
Previous radiotherapy to the chest or breasts
Not physically active
Overweight
HRT for >5 yrs
Pregnancy after 30, not breastfeeding and never having a full term pregnancy
Drinking alcohol
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36
Q

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

A

Early menstrual cycle onset (<12)

Menopause >55

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37
Q

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

A

Cancer developing in ducts and staying there

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38
Q

Why do the cancer cells not spread more in DCIS?

A

Not yet developed the ability to spread

39
Q

What is lobular breast carcinoma in situ?

A

Abnormal cells form in the milk glands

40
Q

Is lobular breast carcinoma in situ cancer?

A

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

41
Q

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

A

Good

42
Q

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

A

Poor

43
Q

How are estrogen and progesterone receptor negative cancers treated?

A

Hormonally

44
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

45
Q

What is fulvestrant?

A

Analogue of estradiol

46
Q

How does fulvestrant work?

A

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

47
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

48
Q

How does tamoxifen work?

A

Binds to the ER at the ligand binding site

49
Q

Is tamoxifen an agonist or an antagonist?

A

Agonist in uterus but antagonist in breast tissue

50
Q

What happens to tamoxifen bound ER?

A

Doesnt fold properly and AF2 domains do not function,

51
Q

Where does estradiol normally bind to the ER?

A

Deep within a pocket in the receptor

52
Q

What happens when estradiol binds to ER?

A

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

53
Q

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

A

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

54
Q

Where does estrogen come from in post-menopausal women?

A

Peripheral conversion of androgens by blood vessels

55
Q

Where is the aromatase enzyme present?

A

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

56
Q

What is a type 1 aromatase inhibitor?

A

Exemestane

Androgen analogue that binds nearby to aromatase

57
Q

What is an example of a type 1 aromatase inhibitor?

A

Exemestone

58
Q

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

A

Rate of de novo aromatase synthesis

59
Q

What is an example of a type 2 aromatase inhibitor?

A

Mastozole

60
Q

What do type 2 aromatase inhibitors contain?

A

Functional group within the ring structure that binds to the haem iron of cytochrome P450

61
Q

What is the main function of normal prostate gland tissue?

A

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

62
Q

What type of gland is a prostate gland?

A

Exocrine

63
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

64
Q

What is prostatitis?

A

Prostate inflammation due to infection

65
Q

What are the two types of dysregulated prostate growth?

A

Benign - benign prostatic hyperplasia

Malignant - prostate cancer

66
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
67
Q

Where does prostate cancer start?

A

Luminal epithelium tissues

68
Q

What does hyperproliferation of the luminal epithelium cause?

A

Prostate intraepithelial neoplasia

69
Q

How can prostate cancer be detected?

A

Digital rectal examination
PSA test (prostate antigen blood test)
Ultrasound

70
Q

What are the classes of prostate cancer?

A

T1-4,
N0-3,
M1a-c

71
Q

What is a T1 tumour?

A

Small localised tumour

72
Q

What is a T2 tumour?

A

Palpable tumour

73
Q

What is a T3 tumour?

A

Escape from prostate gland

74
Q

What is a T4 tumour?

A

Local spread to pelvic region

75
Q

What is a N0 tumour?

A

No cancer in any lymph nodes

76
Q

What is a N1 tumour?

A

One positive lymph node <2cm big

77
Q

What is a N2 tumour?

A

> 1 positive lymph node or one 2-5 cm big

78
Q

What is a N3 tumour?

A

Any positive lymph node >5cm across

79
Q

What is a M1a tumour?

A

Non-regional lymph nodes

80
Q

What is a M1b tumour?

A

Bone

81
Q

What is a M1c tumour?

A

Other sites

82
Q

What is the gleason grading system used for?

A

To help evaluate the prognosis of men using prostate biopsy samples

83
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
84
Q

What are the treatments for prostate cancer?

A

Watchful waiting
Radical prostatectomy
Radical radiotherapy
Hormone therapy

85
Q

What are the risk factors for prostate cancer?

A 
Age
Ethnicity
Family history
Inherited BRCA1/2 gene
Men with lynch syndrome
Diet
Obesity
Chemical exposures
Inflammation of the prostate
STIs
86
Q

What is pten?

A

Phosphatase that antagonises the phosphatidylinositol 3-kinase signalling pathway

87
Q

What does loss of pten result in?

A

Increased growth function signalling

88
Q

How does TMP-RSS2 ERG fusion cause prostate cancers?

A

Androgen receptor drives proto-oncogene ERG which leads to inappropriate gene activation

89
Q

What does abiratrone acetate do?

A

Inhibits testosterone synthesis in the adrenal gland

90
Q

What are finasteride and dutasteride?

A

5 alpha reductase inhibitors

91
Q

What are some examples of anti-androgen drugs?

A

Bicalutamide
Enzalutamide
Flutamide
Nilutamide

92
Q

What are 5 alpha reductase inhibitors commonly used for?

A

Benign prostate hyperplasia

93
Q

What happens to hormone therapies over time?

A

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

94
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

Molecular Basis Of Disease/ Microbiology And Immunology (57 decks)

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