Cancer as a Disease – Breast Cancer Flashcards
What is special about the breast as an organ?
It is the only organ that develops after birth
Where do the vast majority of breast cancers originate?
In the luminal epithelium of the breast (> 90%)
Describe the two layers of epithelial cells in the mammary gland.
Luminal epithelium
Myoepithelium
What is found between the tubules?
Fatty stromal cells
What is special about the myoepithelial cells?
They have a contractile phenotype
Where are oestrogen receptors expressed in the breast?
They are ONLY expressed by luminal cells
But not all luminal cells express oestrogen receptors (only about 10-15%
Describe the response to oestrogen in a normal breast.
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
How is this response different in breast cancer?
The cells displaying oestrogen receptors directly respond to oestrogen as a growth factor and stimulate their own growth
What is the difference between lobular and medullary carcinoma?
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
What specific type of breast cancer accounts for almost 80% of breast cancers?
Infiltrating ductal carcinoma
What percentage of breast cancers is ER positive?
80%
State some risk factors for breast cancer.
Early age of onset of menstruation Late age to menopause Age to first full-time pregnancy Some contraceptive pills Some HRT
Where is the oestrogen receptor normally located?
It is a cytosolic receptor
It is found in the cytosol bound to a heatshock protein
What happens when oestrogen binds to ER?
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
What are the most important target genes for the ER transcription factor?
Progesterone receptor
Cyclin D1
c-myc
TGF-alpha
Why does high dose therapy with synthetic oestrogens cause breast tumour regression in post-menopausal women with breast cancer?
High-dose therapy overstimulates the hormonal system leading to downregulation of ER so the cells are no longer responsive to oestrogen
How does the presence of ER affect prognosis
GOOD prognosis in women
Worse prognosis in male breast cancer
What are three methods of reducing oestrogen action in the breast?
Ovarian suppression
Blocking oestrogen production by enzymatic inhibition
Inhibiting oestrogen responses
At what point during the menstrual cycle is oestrogen at its highest?
End of the follicular phase
How do post-menopausal women make oestrogen?
Aromatisation of androgens
What are two methods of ovarian ablation?
Surgical oophorectomy
Ovarian irradiation
What are the problems associated with these methods?
They are irreversible
Describe a reversible and reliable medical ovarian ablation technique.
LHRH agonists bind to LHRH receptors in the pituitary leading to receptor downregulation and suppression of LH release and inhibitionof ovarian function, including oestrogen production
Give an example of a LHRH agonist.
Goserelin
Buserelin
Triptorelin
Leuprolife
Name an important ER receptor blocker.
Tamoxifen
What is a SERM?
Selective oestrogen receptor modulator
Why is tamoxifen considered a SERM?
It is anti-oestrogenic in the breast
It is oestrogenic in bone and cardiovascular system
Name a drug that is a pure anti-oestrogen, showing no oestrogen like activity at all.
Faslodex
What is raloxifene?
A SERM – it is oestrogenic in bone and anti-oestrogenic in the breast and uterus
What are the problems associated with tamoxifen?
Increased incidence of endometrial cancer (oestrogenic in the uterus)
Increased risk of stroke, DVT, cataracts
Which adrenal hormones are aromatised in post-menopausal women?
Androstenedione (and testosterone, to a lesser extent)
What type of oestrogen is produced in aromatisation?
Oestrone
What does the aromatase complex consist of?
CYP450 heme containing protein
NADPH CYP450 reductase
What are the two types of aromatase inhibitor?
Suicide inhibitors
Competitive inhibitors
How do suicide inhibitors work?
They initially compete with the natural substrate for the active site
The enzyme then specifically acts on the inhibitor to yield reactivealkylating species, which form covalent bonds at or near the active site of the enzyme
Through this mechanism the enzyme is irreversibly inactivated
Give an example of a suicide inhibitor.
Exemestane
Give an example of a competitive aromatase inhibitor.
Anastrozole
What can progestin therapy be used for?
Metastatic breast cancer
What is the main progestin used for metastatic breast cancer?
Megestrol acetate
What is a big problem with endocrine therapy?
Resistance develops
Women in which age range are targeted for breast cancer screening? How often are they asked to go for screening?
50-64 yrs (this is being extended to 70 yrs)
Every 3 years
What proportion of breast tumours are first spotted by the women themselves?
> 90%
