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 via production of GF’s by the luminal cells expressing receptors
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%
- immunohistochemical staining using AB’s against the human OR (oestrogen receptor)
- this stain marks nucleus as OR is a steroid receptor
State some risk factors for breast cancer.
- Early menstruation
- Late age to menopause
- Age at first full-time pregnancy
- Contraceptive pills
- HRT
Where is the oestrogen receptor normally located?
It is a cytosolic receptor
It is found in the cytosol bound to a heatshock protein to form a dimer
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 (PR)
- Cyclin D1
- C-myc
- TGF-alpha (Transforming growth factor 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
increased level of expression of ER:
GOOD prognosis in women
Worse prognosis in male breast cancer
What are three methods of reducing oestrogen action in the breast in endocrine therapy?
- 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
2. Ovarian irradiation
What are the problems associated with these methods of ovarian ablation?
morbidity and irreversibility
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
(competitive inhibitor of estradiol binding to the ER)
-negates effect of oestrogen’s so cell is arrested at G1 phase
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?
- initially compete with the natural substrate (androstenedione and testosterone) for the active site to aromatase
- 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%
How do competitive inbitors work?
Binds reversibly to aromatase
What is the main source of oestrogen in postmenopausal women?
Conversion of adrenal hormones androstenedione and testosterone to oestrone, rather than from ovaries directly
Give the main three hormonal targets used in the treatment of breast cancer
- LHRH agonist
- Aromatase inhibitor
- Antioestrogens
What is the main progestin? What is the use of progestin in cancer?
Progesterone
-endocrine treatment of uterine and breast cancer with clinically proven antineoplastic properties.
What is the principal progestin used for metastatic breast cancer?
Megestrol acetate
