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Molecular Basis Of Disease > 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 chemical messenger that is made by specialist cells, usually within an endocrine gland, and it is released into the blood stream to have an effect in another part of the body.

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2
Q

Where are the endocrine glands in the body?

A

Brain - pineal gland, hypothalamus and pituitary glands

Thyroid

Thymus

Pancreas

Adrenal cortex + kidneys

Male (testies) female (ovaries)

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3
Q

What are the 3 main classes of hormones?

A

Steroids- lipid soluble small molecules (testosterone)

Peptide/proteins (insulin)

Modified amino acids/ amine hormones (adrenaline)

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4
Q

What are steroid hormones synthesised from?

A

Cholesterol (ingested or synthesised de novo in the body)

Basic four ring steroid backbone structure.

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5
Q

Describe the process of steroid synthesis

A

Cholesterol > adrenal cortex > gonadal tissues

  • main corticosteroids and minerals corticosteroids synthesised in the adrenal cortex
  • androgenic and estrogenic precursors released into the bloodstream
  • Androgens and oestrogens produced in target tissues
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6
Q

Give some examples of steroid hormone classes?

A

Androgen (testosterone)

Estrogen (estradiol)

Progestogen (progesterone)

Corticosteroid (cortisol)

Mineral corticosteroids (aldosterone)

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7
Q

What are sex hormones?

A

Are produced by gonads (ovaries and testies)

Responsible for sexual dimorphism between male and female

Responsible for development of the secondary characteristics (eg. Body hair, growth spurt, breast growth)

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8
Q

What are the. 3 main examples of sex hormones?

A

Testosterone

Estrogen

Progesterone

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9
Q

What is the effect of oestrogen on females?

A

Controls the menstrual cycle

Breast tissue development

Fertility

Reproductive organ development

Secondary sexual characteristics

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10
Q

What is the effect of testosterone in males?

A

Controls reproductive and supportive organs

Development of sexual characteristics in men (deepening of the voice, nobody hair)

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11
Q

How do steroid hormones function?

A

Systemically - having effects on several tissues at once

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12
Q

What is the role of steroid hormones in cancer?

A

Steroid hormones can still influence cell growth and function in breast and prostate cancer

Consequently how the disease develops and progresses

The dependence of these tissues on steroids can be exploited when it comes to treatment

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13
Q

What are the 2 most common cancers in the uk?

A

Breast cancer

Prostate cancer

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14
Q

What are the structural domains of steroid hormones and how do they contribute to they’re function?

A

Small lipophillic molecule - enter cells by passing through plasma membrane

Bind to nuclear receptors

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15
Q

How are steroid hormones divided into classes?

A

All steroids bind to a unique nuclear receptor

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16
Q

Describe how steroid hormones work?

A
  1. Steroid hormones in the blood enter cells by simple diffusion
  2. Once inside the cell cytoplasm it binds to a nuclear receptor
  3. Steroid hormone binding causes a conformational change in the receptor - causing it to become activated
  4. The steroid hormone complex then translocated into the nucleus
  5. In the nucleus the steroid receptor binds to DNA at specific binding sites (steroid response elements)
  6. Steroid response elements are short sequences of DNA found in the promoter region of steroid response genes
  7. Steroid responsive genes are switched on and unregulated
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17
Q

What is a ligand blinding domain (LBD)?

A

Binds specific steroid molecules with high affinity

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18
Q

What is a DNA binding domain (DBD)?

A

Binds specific DNA sequences

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19
Q

What are the key components of nuclear receptor?

A

Ligand binding domain (LBD)

DNA binding domain (DBD)

Activation function domain (AF1 and AF2)

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20
Q

What is activation function domain (AF1 and AF2)

A

Recruits gene activation machinery, some receptors have a secondary AF2 domain towards C terminal

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21
Q

What are the key characteristics of nuclear receptors?

A

Receptors bind steroid hormones they are activated

  • they are called ligand-activated receptors
  • binding of steroids to the ligand binding domain causes a physical reconstructing of the polypeptide chains in the receptor, activating it
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22
Q

Describe how transcription factors are activated by ligands

A
  1. Ligand binding to the ligand binding site causes a shift in a alpha helix, activating the receptor
  2. Receptor dimerises, moves into the nucleus and binds to specific DNA sequences
  3. Receptor then recruits DNA modifying enzymes to promoters of hormone responsive genes
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23
Q

What are the 2 zinc fingers domains in the DNA binding domain?

A

Which are essential for sequence specific DNA binding domains

C1 zinc finger - specific DNA sequence binding

C2 zinc finger - interaction with the DNA phosphate backbone

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24
Q

What do hormones responsive genes include?

A

Tissue specific genes

Cell cycle

Proliferation genes

Genes involved in tissue development and differentiation

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25
Q

What are hormone response elements?

A

Are specific DNA sequences found in the promoters of hormone responsive genes

Many are palindromic

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26
Q

Describe the nuclear receptor super family

A

48 nuclear receptor genes

All share a common domain structure (are thought to arise from a common evolutionary ancestor)

They all share a structure that is actives by ligand binding

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27
Q

What is the female breast?

A

Apocrine gland that produces milk used to feed an infant

The breast is composed of glands and ducts, which produce the fatty breast milk

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28
Q

What is the female breast comprised of?

A

Milk producing glands are organised into 15-20 lobes

Within each lobe are lobules where milk is produced?

Milk travels through tiny tubes called ducts

The ducts connect together and become larger ducts and eventually exit the skin via the nipple

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29
Q

What are exocrine glands?

A

Secrete substances out onto a surface or cavity via ductal structure

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30
Q

What are endocrine glands?

A

Secrete substances directly into the bloodstream

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31
Q

What are apocrine glands?

A

Specialised exocrine glands in which a party of cells cytoplasm breaks of releasing contents

32
Q

What are the 2 components of mammillary epithelium?

A

Luminal
- form a single layer of polarised epithelium around ductile lumen.
- luminal cells produce milk during lactation

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

33
Q

What are the two major phases of mammillary gland development?

A

Hormone independent from embryonic development up to puberty

Hormone dependent thereafter during puberty, menstrual cycle and pregnancy

34
Q

What is the role of Estrogen in normal breasts

A

Drives the expression og genes involved in cellular proliferation and differentiation

During puberty- ductal elongation and triggers side branching

Adult Oestrogen - allows for the maintenance for mammary gland tissue + primes tissue for effects of progesterone during pregnancy for milk production

35
Q

What is breast cancer?

A

Tumour forms in the breast

Breast cancer starts most commonly in the cells that line the milk ducts

1/8 women may develop it in they’re lifestyle

Main risks are age, lifestyle, and genetic familial factors

36
Q

Describe the aetiology of breast cancer

A

Age - risk factor for breast cancer increases with age (most after 50)

Genetic mutations - people with genes BRAC1 and BRAC2 are at higher risk of developing breast and ovarian cancer

Reproductive history - early onset of menstrual cycle before 12 years + starting menopause at 55yrs + pregnancy after 30 years + never having full term pregnancy

Previous treatment using radiotherapy to the chest or breasts before age 30 have higher risk of getting breast cancer late in life

Not being physically active

Overweight or obese

Taking hormones

Drinking alcohol

37
Q

What is ductal breast carcinoma in situ (DCIS)?

A

Cancer cells develop within the ducts of the breast but remain within the ducts

Cancer cells have not developed the ability to spread outside these ducts into the teh surrounding breast tissue

38
Q

What is lobular breast carcinoma in situ (LCIS)?

A

A uncommon condition in which abnormal cells form in the milk glands (lobules) in the breast

Isn’t cancer but being diagnosed could increase ur risk of developing breast cancer

39
Q

Where do the majority of breast cancers arise?

A

From luminal cells (epithelial cells of the lumen)

Express the oestrogen receptor (ER)

40
Q

What is the difference between ER positive and ER negative breast cancers?

A

Majority are ER positive and have a good prognosis

ER negative have a relatively poor prognosis and cannot be treated hormonally so patients are given more conventional therapies

41
Q

What is the role of progesterone in breast cancer?

A

Progesterone receptor is a indicator of Estrogen activity

Progesterone is becoming more of a target for cancer therapy as in some subtypes it may reduce cell growth

42
Q

What does the role of ER have in breast cancer?

A

The ER signalling pathway is subverted and becomes uncontrolled

ER ability to bind to DNA and open chromatin is used to transcribe many genes and mRNAs

ER then governs cancer cell proliferation and controls many genes involved in metastasis, invasion and adhesion.

43
Q

How can ER be targeted in breast cancer treatment?

A

Breast cancer cells are Estrogen sensitive and dependent meaning Estrogen are essential for driving the growth of breast cancer cells.

Inhibiting Estrogen signalling inhibits cancer growth

44
Q

How is ER signalling inhibited in breast cancer patients?

A

Biopsy samples are analysed for ER expression to determine weather it’s positive or negative

Specific treatments are given to block ER activity

45
Q

How does the Estrogen signalling pathway work?

A
  1. Bind to receptor
  2. AF1 and AF2 activated - recruited proteins for gene activation
  3. Full gene transcription - breast cancer growth
46
Q

How does fulvestrant (Faslodex) inhibit the ER pathway?

A

It’s a analogue of estradiol

Has a greater binding affinity

Acts as a competitive inhibitor for the binding of estradiol to ER - impairs receptor dimerisation and translocation

The ER implement that enters the nucleus is transcriptionally inactive because both AF1 and AF2 are disabled

The complex is unstable, resulting in accelerated degradation of the ER protein

47
Q

How does Tamoxifen inhibit the ER pathway?

A

Binds the ER at the ligand binding site

Tamoxifen is a partial agonist but does not cause the full activation of ER - activates ER in liver and uterus but acts as a ANTAGONIST in breast tissue

Tamoxifen is a selective Estrogen receptor modulator (SERM)

Tamoxifen bound ER does not fold and AF2 domain doesn’t function

48
Q

What is the process by which Tamoxifen Bound ER inhibits the ER signalling pathway?

A

Normally, estradiol binds deep within a pocket in the receptor and is covered by a loop of protein chain which activates cell growth

When tamoxifen binds to ER ligand binding site - partially active

the extra tail of tamoxifen is too bulky and the receptor loop is unable to adopt its active conformation.

Receptor undergoes a conformational change only activating the AF1 domain.

Partially activating transcription

49
Q

What is a alternative source of Oestrogens during menopause?

A

Conversion of androgens by aromatase enzyme

Aromatase is present in many organs (brain, skin, bone)

50
Q

What is the type 1 aromatase inhibitor mechanism?

A

Androgen analogues

Bind irreversibly to aromatase - “suicide inhibitors”

Duration of inhibitory effect is primarily dependent on the rate of de novo synthesis of aromatase

51
Q

What is the type 2 aromatase inhibitor mechanism?

A

Contains a functional group within the ring structure that binds the heme iron of the cytochrome P450 (of aromatase)

Interferes with the hydroxylation reactions

52
Q

What is the function of the prostate?

A

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

Luminal epithelial cells surrounding duct lumens
Basal epithelial cells

53
Q

What are the phases of normal prostate development?

A
  1. Hormone independent from embryonic until puberty
  2. Enlargement during puberty
  3. Hormone-dependent maintenance thereafter in adulthood
  4. Reactivation of prostate growth in old age - prostate cancer
54
Q

What are the symptoms of prostate cancer?

A
  • frequent trips to urinate
  • poor urinary stream
  • urgent need to urinate
  • hesitancy whilst urinating
  • lower back pain
  • blood in the urine
55
Q

Where does prostate cancer start?

A

Originate in luminal epithelial cells - hyper proliferation

56
Q

What are the three ways to detect prostate cancer?

A

1) digital rectal examination (DRE)

2) PSA test

3) ultrasound

57
Q

What are stages of prostate cancer?

A

T1 - small, localised tumour

T2 - palpable tumour

T3 - escape from prostate gland

T4 - local spread to pelvic region

58
Q

What does the N number represent in lymph node tumours?

A

N0 - no cancer cells found in any lymph nodes

N1 - 1 positive lymph node < 2 cm across

N2 - >1 positive lymph node one between 2-5cm

N3 - any positive lymph node > 5 cm across

59
Q

What does the M number represent in metastasis ?

A

M1a - Non-regional lymph nodes

M1b - bone

M1c - other sites

60
Q

What does prostate gland look like under a microscope?

A

Loss of glandular structure / irregular structure

61
Q

Describe how the Gleason grading system used to asses prostate cancer

A

Prostate biopsy samples are examined by a clinical histologist

Cancer staging predicts prognosis

Cancers with higher Gleason score are more aggressive and have a worse prognosis

62
Q

What are the four treatments for prostate cancer?

A

“Watchful waiting” - low grade tumour, older patients

Radical prostate - stage T1 or T2

Radical radiotherapy - external up to T3 or internal implants for T1/2

Hormone therapy - +/- prosectomy or radial radiotherapy, metastasis prostate

63
Q

What are the risk factors for prostate cancer?

A

Age - rare in men younger than 40

Race/Ethnicity - develops more often in African-American men and in Caribbean men

Geography - most common in North America, north-western Europe, Australia, and on Caribbean islands

Family history - mostly occur in men without a family history of it but can run in some families

Gene changes/ inherited - inherited BRAC1 and BRAC2 gene mutations or lynch syndrome

Diet - a lot of dairy products may play a role

Obesity

64
Q

What genetic changes are involved in prostate cancer?

A

Somatic copy number alterations - gain or loss of genetic material

Structural rearrangements - improper repair of DNA breaks leads to chromosome rearrangements

Point mutations - changes in specific nucleotides - ulterior gene products

Single nucleotide polymorphisms (SNPs) - variations in a single nucleotide between individual’s or chromosomes

miRNA - small, non-coding RNA molecules

65
Q

What is PTEN?

A

A phosphatase that antagonises the 3-kinase signalling pathway

PTEN is the Only Known 3 phosphatase counteracting the PI3K/AKT pathway

Loss of PTEN results in increased growth factor signalling

66
Q

Where are testosterone receptors located in the prostate gland?

A

Brown staining for androgen receptor expression in the luminal epithelial cells

In cytoplasm

Associated with chaperone proteins

67
Q

Describe the androgen receptor AR signalling pathway

A
  1. Testosterone is converted to a more potent agonist as it enters prostate cells
  2. Dihydrotestosterone (DHT) then binds to AR
  3. Dimerisation occurs
  4. DNA binding
  5. COACTIVATOR RECRUITMENT
68
Q

How can AR be a target for prostate cancer treatment?

A

Prostate gland is androgen sensitive and dependent tissue

Switching of AR signalling, switches off cancer growth

69
Q

Describe the inhibition of testosterone synthesis for prostate cancer

A

adrenal androgen production can be inhibited

depriving the testes of testosterone

Eg.
Abiraterone acetate - prevents cholesterol being converted to adrenal androgens
Goserelin - super agonist
Abarelix - antagonist

70
Q

Describe the inhibition of testosterone conversion to DHT

A

5 alpha reductase

Inhibit the conversion of testosterone to DHT

Used for begnin hyperplasia

71
Q

Describe the inhibition of androgen binding to the receptor

A

Competitive inhibition of androgen binding to the receptor

Helix 12 cannot fold over

Creating inactive transcription factor

Eg. Flutamide, Nilutamide

72
Q

How effective are hormone therapies for cancer?

A

Normally hormone therapies work well BUT over time these therapies begin to fail and patients relapse with hormone refractory cancers

73
Q

How can hormone overproduction occur?

A

Some breast and prostate tumour start to synthesis their own steroid hormones

74
Q

How do ligand binding site mutations allow other hormones to bind?

A

Ligand binding site mutations make the receptor promiscuous

75
Q

Describe the process of receptor amplification

A
  1. Signal amplification and increased sensitivity to low hormone levels
  2. Receptor phosphorylation / activation in the absence of ligand
  3. Androgen receptor transcription variants - activation in absence of ligand
  4. Receptor bypass - unknown mechanisms
  5. Receptor cofactor amplification - signal from steroid receptors in response to a low level of steroid hormone
  6. Antagonist become agonist via LBD mutations - can become potent activators of a mutant androgen receptor

Molecular Basis Of Disease (32 decks)

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