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Y2 Cancer (MCD) > Cancer as a Disease – Breast Cancer > Flashcards

Cancer as a Disease – Breast Cancer Flashcards

1
Q

What is special about the breast as an organ?

A

It is the only organ that develops after birth

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2
Q

Where do the vast majority of breast cancers originate?

A

In the luminal epithelium of the breast (> 90%)

In the terminal duct lobular unit

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3
Q

Describe the two layers of epithelial cells in the mammary gland.

A

Luminal epithelium

Myoepithelium

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4
Q

What is found between the tubules?

A

Fatty stromal cells

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5
Q

What is special about the myoepithelial cells?

A

They have a contractile phenotype

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6
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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7
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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8
Q

How is the oestrogen response different in breast cancer?

A

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

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9
Q

What is the difference between lobular and medullary carcinoma?

A

Lobular – the tumour has some resemblance of the architecture of the gland (there are tubules of some form)

Medullary – the tumour cells don’t look anything like the epithelial cells from the mammary gland

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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

What percentage of breast cancers is ER positive?

A

80%

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12
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

Some HRT

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13
Q

Where is the oestrogen receptor normally located?

A

It is a cytosolic receptor

It is found in the cytosol bound to a heatshock protein

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14
Q

What happens when oestrogen binds to ER?

A

The oestrogen binds to ER and then two ERs 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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15
Q

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

A

Progesterone receptor
Cyclin D1
c-myc
TGF-alpha

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16
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

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17
Q

How does the presence of ER affect prognosis

A

GOOD prognosis in women

Worse prognosis in male breast cancer

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18
Q

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

A

Ovarian suppression

Blocking oestrogen production by enzymatic inhibition

Inhibiting oestrogen responses

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19
Q

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

A

End of the follicular phase

20
Q

How do post-menopausal women make oestrogen?

A

Aromatisation of androgens

21
Q

What are two methods of ovarian ablation?

A

Surgical oophorectomy

Ovarian irradiation

22
Q

What are the problems associated with these methods?

A

They are irreversible

23
Q

Describe a reversible and reliable medical ovarian ablation technique.

A

LHRH agonists bind to LHRH receptors in the pituitary leading to receptor downregulation and suppression of LH release and inhibition of ovarian function, including oestrogen production

24
Q

Give an example of a LHRH agonist.

A

Goserelin
Buserelin
Triptorelin
Leuprolife

25
Q

Name an important ER receptor blocker.

A

Tamoxifen

26
Q

What is a SERM?

A

Selective oestrogen receptor modulator

27
Q

Why is tamoxifen considered a SERM?

A

It is anti-oestrogenic in the breast

It is oestrogenic in bone and cardiovascular system

28
Q

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

A

Faslodex

29
Q

What are the problems associated with tamoxifen?

A

Increased incidence of endometrial cancer (oestrogenic in the uterus)

Increased risk of stroke, DVT, cataracts

30
Q

Which adrenal hormones are aromatised in post-menopausal women?

A

Androstenedione (and testosterone, to a lesser extent)

31
Q

What type of oestrogen is produced in aromatisation?

A

Oestrone (E2)

32
Q

What catalyses aromatisation?

A

Aromatase enzyme complex:

CYP450 heme containing protein
NADPH CYP450 reductase

33
Q

What are the two types of aromatase inhibitor?

A 
Suicide inhibitors  (Type I)
Competitive inhibitors (Type II)
34
Q

How do suicide inhibitors work?

A

They initially compete with the natural substrate for the active site

The enzyme then specifically acts on the inhibitor to yield reactive alkylating species, which form covalent bonds at or near the active site of the enzyme

Through this mechanism the enzyme is irreversibly inactivated

35
Q

Give an example of a suicide inhibitor.

A

Exemestane

36
Q

Give an example of a competitive aromatase inhibitor.

A

Anastrozole

37
Q

What can progestin therapy be used for?

A

Metastatic breast cancer

38
Q

What is the main progestin used for metastatic breast cancer?

A

Megestrol acetate

39
Q

What is a big problem with endocrine therapy?

A

Resistance develops

40
Q

Women in which age range are targeted for breast cancer screening? How often are they asked to go for screening?

A

50-64 yrs (this is being extended to 70 yrs)

Every 3 years

41
Q

What proportion of breast tumours are first spotted by the women themselves?

A

> 90%

42
Q

What are the most common types of breast cancer?

A

Invasive ductal carcinoma (up to 80% of all BC)

Invasive lobular carcinoma (5-15%)

43
Q

What are the long term side effects of tamoxifen?

A

Endometrial thickening

Hyperplasia

Fibroids

44
Q

What is a drug similar to tamoxifen?

A

Toremifene

45
Q

What is raloxifene?

A

Antitumour agent used for breat cancer treatment

Very oestrogenic in bone

Not oestrogenic in uterus

46
Q

Where does the aromatisation conversion occur?

A

extra-adrenal or peripheral sites such as fat, liver, and muscle.

47
Q

What is the breast cancer resistance to endocrine therapy due to?

A

NOT due to tumours becoming ER-independent

Resistant tumours have mutated ER

Y2 Cancer (MCD) (16 decks)

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