Cancer as a Disease – Breast Cancer

Question 1

What is special about the breast as an organ?

Answer 1

It’s the only organ that develops after birth

Question 2

Where do the vast majority of breast cancers originate?

Answer 2

Luminal epithelium of the breast (> 90%)

Question 3

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

Answer 3

Luminal epithelium

Myoepithelium

Question 4

What is found between the tubules in the mammary gland?

Answer 4

Fatty stromal cells

Question 5

What is special about the myoepithelial cells?

Answer 5

They have a contractile property, thus can squeeze the luminal epithelial cells when full of milk globules in lactation

Question 6

Where are oestrogen receptors expressed in the breast?

Answer 6

ONLY expressed by luminal cells

Not all luminal cells express oestrogen receptors (only ~ 10)

Question 7

Describe the response to oestrogen in a normal breast.

Answer 7

Response to oestrogen is to stimulate growth
Cells that express oestrogen receptors do NOT grow in response to oestrogen
Act as a beacon + produce growth factors that stimulate the growth of nearby cells

Question 8

How is the response to oestrogen different in breast cancer?

Answer 8

Cells displaying oestrogen receptors directly respond to oestrogen as a growth factor + stimulate their own growth

Question 9

What is the difference between lobular and medullary carcinoma?

Answer 9

Lobular: tumour has some resemblance of the architecture of the gland (tubules of some form)
Medullary: tumour cells don’t look anything like the epithelial cells from the mammary gland

Question 10

What specific type of breast cancer accounts for almost 85% of breast cancers?

Answer 10

Infiltrating ductal carcinoma

Question 11

What percentage of breast cancers is ER positive?

Answer 11

80%

Question 12

State 7 risk factors for breast cancer.

Answer 12

Early age of onset of menstruation  
Late age to menopause  
Age to 1st full-time pregnancy  
Some contraceptive pills  
Some HRT
Obesity
Diet

Question 13

Where is the oestrogen receptor normally located?

Answer 13

Cytosolic receptor

Bound to a heatshock protein

Question 14

What happens when oestrogen binds to ER?

Answer 14

Oestrogen binds to ER + then 2 ERs dimerise + translocate to the nucleus (with oestrogen bound)
Dimer binds to oestrogen response elements in the DNA sequence + regulates transcription

Question 15

What are the 4 most important target genes for the ER transcription factor?

Answer 15

Progesterone receptor
Cyclin D1
c-myc
TGF-alpha

Question 16

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

Answer 16

High-dose therapy overstimulates the hormonal system leading to downregulation of ER so the cells are no longer responsive to oestrogen

Question 17

How does the presence of ER affect prognosis?

Answer 17

GOOD prognosis in women

Worse prognosis in male breast cancer

Question 18

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

Answer 18

Ovarian suppression
Blocking oestrogen production by enzymatic inhibition
Inhibiting oestrogen responses

Question 19

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

Answer 19

End of the follicular phase

Question 20

How do post-menopausal women make oestrogen? Where does this occur?

Answer 20

Aromatisation of androgens
Fatty tissue (+ liver + muscles)

Question 21

What are 2 methods of ovarian ablation?

Answer 21

Surgical oophorectomy

Ovarian irradiation

Question 22

What are the problems associated with Surgical oophorectomy and Ovarian irradiation?

Answer 22

They are irreversible

Question 23

Describe a reversible and reliable medical ovarian ablation technique.

Answer 23

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

Question 24

Name an important ER receptor blocker.

Answer 24

Tamoxifen

Question 25

What is a SERM? | Why is tamoxifen considered a SERM?

Answer 25

Selective oestrogen receptor modulator Anti-oestrogenic in the breast Oestrogenic in bone + cardiovascular system

Question 26

Name a drug that is a pure anti-oestrogen, showing no oestrogen like activity at all. What are the negatives of this drug?

Answer 26

Faslodex | Blocks oestrogen everywhere in the body, thus increases risk of osteoporosis + CVD

Question 27

What is raloxifene?

Answer 27

A SERM: it is oestrogenic in bone + anti-oestrogenic in the breast + uterus

Question 28

What are the problems associated with tamoxifen?

Answer 28

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

Question 29

Which adrenal hormones are aromatised in post-menopausal women?

Answer 29

Androstenedione (+ testosterone, to a lesser extent)

Question 30

What does the aromatase complex produce from androstenedione?

Answer 30

Oestrone Sulphate

Question 31

What does the aromatase complex consist of?

Answer 31

cytochrome P450 heme containing protein | NADPH cytochrome P450 reductase

Question 32

What are the two types of aromatase inhibitor?

Answer 32

Irreversible | Reversible

Question 33

How do Irreversible aromatase inhibitors work?

Answer 33

Bind to active site of aromatase complex Causes formation of alkylating species + covalent bonds Irreversibly inactivates the enzyme

Question 34

Give an example of an aromatase inhibitor

Answer 34

Exemestane

Question 35

Give an example of a reversible aromatase inhibitor.

Answer 35

Anastrozole

Question 36

What can progestin therapy be used for?

Answer 36

Metastatic breast cancer

Question 37

What is the main progestin used for metastatic breast cancer?

Answer 37

Megestrol acetate

Question 38

What is a big problem with endocrine therapy?

Answer 38

Resistance develops | Relapse occurs

Question 39

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

Answer 39

50-64 yrs | Every 3 years

Question 40

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

Answer 40

> 90%

Question 41

What may have contributed to the rising incidence but falling mortality of breast cancer?

Answer 41

Early diagnosis (public health message to self examine) Chemo/ Radiotherapies can now be more focussed + effective Availability of hormonal therapies

Question 42

What is the major treatment approach to breast cancer?

Answer 42

Surgery | Followed by chemo/ radiotherapy

Question 43

What is given as adjuvant therapy for breast cancer?

Answer 43

Endocrine therapy | Kills any tumour cells that broke away from the tumour mass/ weren't removed in surgery

Question 44

What are the 3 pathways of endocrine therapy?

Answer 44

Ovarian suppression (pre-menopausal) Blocking oestrogen production by enzymatic inhibition Inhibiting ER

Question 45

How is oestrogen primarily made? (pre-menopausal)

Answer 45

Hypothalamus stimulates the pituitary through LHRH Causes release of LH + FSH Stimulates ovary to make large quantities of oestrogen

Question 46

What is the most common side effect of Tamoxifen therapy?

Answer 46

Hot flushes

Question 47

How do reversible aromatase inhibitors work?

Answer 47

Bind reversibly to active site, competing with androstenedione