Breast cancer Flashcards
What is unique about the breasts development?
It is the only organ that develops after birth
What happens to the breast during puberty?
It develops into a fatty glandular structure
Which part of the breast can develop cancer?
Every part
Where does the majority of breast cancer originate?
> 90% originates in the luminal epithelium
Between the tubules in the breast, what is there?
Fatty stromal cells
What are the two layers of epithelial cells?
Luminal epithelial cells Myoepithelial cells (surrounding the luminal cells)
What phenotype do the myoepithelial cells have?
A contractile phenotype and they will contract when they receive the right hormonal signals
How are myoepithelial cells in the development of the gland?
They are responsible for the formation of the tubules
Where are oestrogen receptors expressed in the breast?
Only by luminal epithelial cells but not all luminal epithelial cells express oestrogen receptors (only 10%)
What is the normal response to oestrogen in a gland?
Stimulate growth
Which cells grow in response to oestrogen normally?
Not the the cells that are oestrogen receptor positive- they act as beacons to produce growth factors that stimulate the growth of nearby cells
Which cells grow in response to oestrogen in breast cancer?
It is the opposite of normal- the oestrogen responsive cells directly respond to oestrogen as a growth factor and stimulates their own growth
What is benign/carcinoma in situ like in terms of cells?
There is proliferation of luminal cells but myoepithelium is still around it- possible precancerous state
What is lobular carcinoma like?
Tumour has some resemblance of the architecture of the gland- there are tubules of some form
What is medullary carcinoma like?
Tumour cells don’t look anything like epithelial cells from mammary gland
What sort of carcinoma are the majority of breast cancers?
Neither medullary or lobular so are just called breast carcinoma
How do you classify breast tumours as ER positive or negative?
Staining tissue samples for ER- it is the nucleus that is being stained because ER is a transcription factor found in the nucleus
What percentage of breast cancers are ER positive?
Over 80%
What risk factors are there for breast cancer?
Life time exposure to oestrogens: Early age of menstruation Late age to menopause Age to first full-term pregnancy Some contraceptive pills Some HRTs
What sort of receptor is ER?
Cytosolic- inside the cell
What is the ER bound to inside the cell?
Heatshock protein forming a dimer
How come oestrogen can pass easily through the cell membrane?
It is highly lipophilic
What does oestrogen do once inside the cell?
It binds to the ER and displaces the heatshock protein, two oestrogen receptors then come together to form a dimer and this dimerised protein is then able to enter the nucleus (with oestrogen bound) and locate DNA sequences in the genome that are response elements for this transcription factor
Why is the dimerisation of the ER significant?
Response elements are present in two halves so each half of the dimer will bind to each half of the response element
What are the most important target genes of this transcription factor?
Progesterone receptor
Cyclin D1
C-myc
TGF-alpha
Which patients with breast cancer will respond to oophorectomy?
1/3 of premenopausal women with advanced breast cancer
What causes breast tumour regression in post-menopausal women?
High dose therapy with synthetic oestrogens- if you overstimulate this hormone system it will result in the down regulation of the ER so the cells are no longer responsive to oestrogen
In what percentage of breast cancers is ER over expressed?
Around 70% of breast cancers
How does the presence of ER affect prognosis?
Increased level of expression of ER is indicative of better prognosis in female but worse in male
What is the cornerstone of breast cancer treatment?
Endocrine therapy:
Ovarian suppression
Blocking oestrogen production by enzymatic inhibition
Inhibiting oestrogen responses
What are the main site of oestrogen production in pre-menopausal women?
Ovaries
What does levels of oestrogen production depend on and when is it at its highest?
Stage of the menstrual cycle- at its highest at the end of follicular stage
How do post-menopausal women make oestrogen?
Aromatisation of androgens in peripheral tissues
What does ovarian ablation aim to do and how is it done?
Eliminate this source of oestrogen and it can be carried out by:
Surgical oophorectomy
Ovarian irradiation
What are the major problems with ovarian ablation?
Morbidity
Irreversibility
How can reversible and reliable medial ovarian ablation be achieved?
Using luteinising hormone releasing hormone agonists
How do LHRH agonists work?
They bind to LHRH receptors in the pituitary leading to receptor down regulation and suppression of LH release and inhibition of ovarian function including oestrogen production
Give examples of LHRH agonists
Goserelin
Buserelin
Triptorelin
Leuprolide
What is tamoxifen?
ER receptor blocker (competitive inhibitor)
What effect does tamoxifen have?
It negates the stimulatory effect of oestrogen causing the cells to be held at the G1 phase of the cell cycle
When is tamoxifen used?
It is the endocrine treatment of choice for metastatic disease in post-menopausal patients
What is the most common side effect of tamoxifen?
Hot flushes
What sort of drug is tamoxifen?
SERM- it is oestrogenic on cardiovascular system- decreases atherosclerotic risk in women however it increases risk of thromboembolic events and can cause endometrial hyperplasia
What is toremifene?
Structural derivative of tamoxifen with similar effects
What is faslodex?
It shows no oestrogen like activity in laboratory tests but is effective in controlling oestrogen stimulated growth- it is a pure anti-oestrogen
How does faslodex offer advantages over tamoxifen?
Decreases tumour cell invasion and stimulation of occult endometrial carcinoma
What is raloxifine?
An anti tumour agent in animals- it is an agonist in bone but no activity in breast or uterus
It is used in treatment of osteoporosis in post-menopausal women
What problems are associated with using tamoxifen in prevention?
Endometrial cancer
Storke
DVT
Cataracts
Where does the conversion of androgens to oestrogen take place?
Extra-adrenal or peripheral sites such as fat, liver and muscle
What catalyses conversion of androgens to oestrogen?
Aromatase enzyme complex
What does aromatase consist of?
Complex containing a CYP450 heme containing protein as well as a flavoprotein NADPH CYP450 reductase
What does aromatase catalyse in the formation of oestrogen?
It catalyses three separate steroid hydroxylations involved in the conversion of androstenedione to oestrone
What is a suicide inhibitor?
Type of aromatase inhibitor that initially competes with natural substate for binding to 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, the enzyme is irreversibly inactivated
Give an example of a suicide inhibitor?
Exemestane
What are the side effects of a suicide inhibitor?
Hot flush, nausea and fatigue
How do competitive inhibitors work?
They bind reversibly to active site of the enzyme and prevent product formation only as long as inhibitor occupies catalytic site
e.g. Anastrozole
What is the dominant naturally occurring progestin?
Progesterone
What does progesterone influence in the breast?
Its effects are complex but it influences both differentiation and proliferation
What are progestins used to treat?
Endocrine treatment of uterine and breast cancer with clinically proven anti-neoplastic properties
What is a problem with endocrine therapies?
A significant percentage of patients presenting with bread cancer and all patients with metastatic disease become resistant to endocrine therapies
What is the breast cancer screening programme like?
It uses mammography to screen all women between 50 and 64 who are registered with GP in UK- it is being extended to 70
Each patient is asked to attend a test once every 3 years
What is the normal patient history of breast cancer?
Lump detected Referred to hospital Examined by surgical team Surgery Tumour examined pathologically See physician ER+ tamoxifen (5 years) or ER- chemotherapy (6 months) Disease free If secondary tumour, no cure
