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Y2 - CANCER > Cancer as a Disease – Breast Cancer > Flashcards

Cancer as a Disease – Breast Cancer Flashcards

1
Q

Where do the vast majority of breast cancers originate?

A
  • In the luminal epithelium of the breast
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2
Q

Describe the two layers of epithelial cells in the mammary gland and say which is the outer layer and which is the inner layer and which one is in contact with the basement membrane

A
  • Myoepithelium - outer layer - in contact with the basement membrane
  • Luminal epithelium - inner layer
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3
Q

What is found between the tubules?

A
  • Fatty stromal cells
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4
Q

What is special about the myoepithelial cells?

A
  • They have a contractile phenotype
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5
Q

Where are oestrogen receptors expressed in the breast?

A
  • They are ONLY expressed by luminal cells
  • But not all luminal cells express oestrogen receptors (only about 10-15%
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6
Q

Describe the response to oestrogen in a normal breast

A
  • The response to oestrogen is to stimulate growth
  • The cell that express oestrogen receptors do NOT grow in response to oestrogen
  • They act as a beacon and produce growth factors the stimulate the growth of nearby cells
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7
Q

Describe the response to oestrogen in cancerous breast tissue - just broad stroke not in terms of the detailed physiology

A
  • The cells displaying oestrogen receptors directly respond to oestrogen as a growth factor and stimulate their own growth
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8
Q

What are the 2 types of breast carcinoma, and describe them

A
  1. Lobular – the tumour has some resemblance of the architecture of the gland (there are tubules of some form), attempt to retain the normal luminal epithelial cells and the tubule
  2. Medullary – the tumour cells don’t look anything like the epithelial cells from the mammary gland
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9
Q

What happens in benign in-situ carcinoma?

A
  • Local proliferation of luminal epithelial cells without loss of myoepithelium
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10
Q

What specific type of breast cancer accounts for almost 80% of breast cancers?

A
  • Infiltrating ductal carcinoma
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11
Q

State some risk factors for breast cancer

A
  • Early age of onset of menstruation
  • Late age to menopause
  • Age to first full-time pregnancy
  • Some contraceptive pills
  • HRT
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12
Q

Where is the oestrogen receptor normally located and in what form is it?

A
  • It is a cytosolic receptor
  • Bound to HSB-90 (heat-shock 90 protein)
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13
Q

What happens when oestrogen binds to ER?

A
  • The oestrogen is very lipophilic so crosses the cell membranes and enters the cytosol
  • It binds to ER, causing displacement of HSB-90 (the heat-shock 90 protein)
  • This allows 2 ERs to dimerise and translocate to the nucleus (with oestrogen bound)
  • The dimer then binds to response elements in the DNA sequence and regulates transcription
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14
Q

What are the most important target genes for the ER transcription factor?

A
  • Progesterone receptor
  • Cyclin D1 (cell-cycle regulator)
  • c-myc (involved in apoptosis)
  • TGF-alpha (a GF directly influencing cellular growth)
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15
Q

Why does high dose therapy with synthetic oestrogens cause breast tumour regression in post-menopausal women with breast cancer?

A
  • High-dose therapy overstimulates the hormonal system leading to downregulation of ER so the cells are no longer responsive to oestrogen - i.e. negative feedback by receptor downregulation
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16
Q

How does the presence of ER affect prognosis

A
  • GOOD prognosis in women
  • Worse prognosis in male breast cancer
17
Q

What are three methods of reducing oestrogen action in the breast?

A
  1. Ovarian suppression - blocking production of oestrogen
  2. Blocking oestrogen production by enzymatic inhibition (blocking aromatase action)
  3. Inhibiting oestrogen responses
18
Q

At what point during the menstrual cycle is oestrogen at its highest?

A
  • End of the follicular phase
19
Q

How do post-menopausal women make oestrogen?

A
  • Aromatisation of androgens
20
Q

1) What are two interventional methods of ovarian ablation (i.e. excluding drugs)?
2) What are the problems associated with these methods?

A

1)

  1. Surgical oophorectomy
  2. Ovarian irradiation

2)

  • They are irreversible
  • Cause infertility
21
Q

Describe an alternative to ovarian ablation which also obliterates oestrogen production but is reversible and reliable

A
  • Medical ovarian ablation
  • LHRH agonists bind to LHRH receptors in the pituitary leading to negative feedback by receptor downregulation and therefore suppression of LH release and inhibition of ovarian function, including oestrogen production
22
Q

Give 4 examples of LHRH agonists

A
  1. Goserelin
  2. Buserelin
  3. Triptorelin
  4. Leuprolife
23
Q

Name an important ER receptor blocker

A
  • Tamoxifen
24
Q

What is a SERM?

A
  • Selective oestrogen receptor modulator
25
Q

Why is tamoxifen considered a SERM?

Why are its selective properties useful and, how can it be detrimental?

A
  • It is anti-oestrogenic in the breast
  • It is oestrogenic in uterus, bone and cardiovascular system
  • By being oestrogenic in bone it is anabolic and doesn’t cause osteoporosis as it would had it also been anti-oestrogenic in bone
  • By being oestrogenic on the CVS, it has a positive, beneficial impact on the lipid profile
  • However, by being oestrogenic in the uterus, it leads to endometrial proliferation - increased risk of endometrial cancer
26
Q

Name a drug that is a pure anti-oestrogen, showing no oestrogen like activity at all

A
  • Faslodex
27
Q

1) What is raloxifene?
2) How is it different to tamoxifen?

A

1)

  • A SERM – it is oestrogenic in bone and anti-oestrogenic in the breast and uterus

2)

  • Different to tamoxifen in that it has anti-oestrogenic effect in the uterus as well, unlike tamoxifen which as an oestrogenic effect in the uterus
28
Q

What are the problems associated with tamoxifen?

A
  • Increased incidence of endometrial cancer (oestrogenic in the uterus)
  • Increased risk of stroke, DVT, cataracts
29
Q

Which adrenal hormones are aromatised in post-menopausal women?

A
  1. Androstenedione
  2. Testosterone
30
Q

What type of oestrogen is produced in aromatisation?

A
  • Oestrone
31
Q

What does the aromatase complex consist of?

A
  • CYP450 heme containing protein
  • NADPH CYP450 reductase
32
Q

1) What are the two types of aromatase inhibitor, give an example of each
2) How do each of these work?

A

1)

  1. Suicide inhibitors - e.g. exemestane
  2. Competitive inhibitors e.g. anastrozole

2)

TYPE 1 - SUICIDE INHIBITORS

  • They initially compete with the natural substrate for the active site
  • The enzyme (aromatase) then acts on the inhibitor to yield reactive alkylating species, which form covalent bonds at or near the active site of the enzyme
  • This irreversibly inactivates the aromatase

TYPE 2 - COMPETITIVE INHIBITORS

  • Literally just compete with the substrates for aromatase
33
Q

What can progestin therapy be used for?

A
  • Metastatic breast cancer
34
Q

What is the main progestin used for metastatic breast cancer?

A
  • Megestrol acetate
35
Q

What is a big problem with endocrine therapy?

A
  • Resistance develops after relapse

Y2 - CANCER (14 decks)

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