Cancer as a Disease: Breast Cancer Flashcards
How many people develop and dies from breast cancer?
1/8 develop
1/5 die
What is happening to the incidence and mortality?
incidence is increasing and mortality is falling – early diagnosis, chemo, hormonal therapies
Where does most breast cancer originate?
luminal epithelium
How is the mammary gland organised?
Between the tubules are fatty stromal cells
There are two layers of epithelial cells:
- Luminal epithelial cells
- Myoepithelial cells – contractile cells
Oestrogen receptors are only expressed by luminal epithelial cells (but not all the luminal cells express the receptor)
What is the normal and breast cancer response to oestrogen?
NORMAL – stimulate growth via production of growth factors by the luminal cells expressing receptors (not the cells themselves)
Breast cancer – REVERSAL – oestrogen-responsive cells directly respond to oestrogen as a GF and stimulate their own growth
What are the types of carcinoma?
Benign/carcinoma-in-situ – proliferation of luminal cells but the myoepithelium is still around it
Lobular carcinoma – resemblance of the architecture of the gland
Medullary carcinoma – no resemblance to the gland
- Majority of cancers are not either lobular or medullary so are just called breast
IDC – infiltrating ductal carcinoma – feature no special histological features – 80% of breast cancers
How are breast cancers stained?
Immunohistochemically staining using ABs against the human OR (oestrogen receptor) - marks the nucleus as OR is a steroid receptor
*>80% of breast cancers are OR+
What are some risk factors for breast cancer?
- lifetime exposure to oestrogen
- early menstruation
- HRT
- late menopause
- contraceptive pill
- pregnancy
What happens at the oestrogen receptor?
- Inside the cell, the OR is bound to a heatshock protein to form a dimer
- Oestrogen (lipophilic) then passes through the membrane, binds to the OR and displaces the heatshock protein. 2 ORs then dimerise
- Dimerised ORs enter the nucleus and bind to the DNA response elements and pull them together (response elements are also in two halves and need a dimer to activate them)
What are some oestrogen regulated genes?
- progesterone receptor (PR)
- cyclin D1
- c-myc
- TGF-a
What is the oestrogen paradox in breast cancer?
Oestrogen can also affect some breast cancers like it affects the normal breast - approx. 1/3rd of premenopausal women will respond to an oophorectomy
Paradoxically, breast cancer in post-menopausal women respond to high-dose oestrogen therapy – due to downregulation of ORs as there is a high concentration of oestrogen
How does OR expression affect prognosis?
- OR expression in females = GOOD PROGNOSIS
- OR expression in males = BAD PROGNOSIS
What are the treatment options?
- Surgery
- Radiation therapy
- Chemotherapy
- Endocrine therapy – the gold-standard or cornerstone treatment:
> Ovarian suppression
> Blocking oestrogen production by enzymatic inhibition
> Inhibition of oestrogen responses
How are the ovaries ablated?
- Surgical oophorectomy
- Ovarian irradiation
- major problems with this is morbidity and irreversibility so there are more medical suppression techniques
What happens in ovarian suppression?
Reversible/reliable medical ovarian ablation is achieved with LHRH (LH-Releasing Hormone) agonists which bind in the pituitary gland and down-regulate and supress LH release and inhibit ovarian function (including oestrogen production)
LHRH examples – Goserelin, Buserelin, Leuprolide, Triptorelin
What are hormonal targets for treatment?
- LHRH agonists
- Aromatase inhibitors – prevent conversion
- Antioestrogens
What is tamoxifen?
OR-blocker or a SERM – competitive inhibitor
- This negates the effects of oestrogens so the cell is arrested at the G1 phase
- Oestrogenic in bone and the CVS (decrease risk of osteoporosis and atherosclerosis risk)
Tamoxifen is the drug of choice for metastatic cancer in post-menopausal patients
Few side effects – bar hot flushes
What are toremifene, faslodex and raloxifene?
Toremifene = analogue of tamoxifen
Faslodex = no oestrogen-like activity but effective at controlling oestrogen-stimulated growth
- Pure anti-oestrogen
- Decreases tumour cell invasion and the stimulation of occult endometrial carcinoma
Raloxifene = anti-tumour agent in animals
- Oestrogenic in bone
- No activity in breast or uterus
- Treats osteoporosis
What have tamoxifen trials shown?
- 38% reduction in overall breast cancer incidence
- No effect on OR-breast cancer incidence
- No association between prevention and patient age
What are the side effects of tamoxifen as a prophylactic drug?
- endometrial cancer
- stroke
- DVT
- cataracts
What is the main source or oestrogen in post menopausal women?
conversion of adrenal hormones (androstenedione and testosterone) -> oestrone
- occurs at the extra-adrenal or peripheral sites – liver, fat and muscle.
** catalysed by aromatase enzyme complex
What is aromatase? What does it do?
complex with:
- Cytochrome P450 haem containing protein
- Flavoprotein NADPH CYP450 reductase
Aromatase catalyses 3 steroid hydroxylations involved in conversion of androstenedione to oestrone
Aromatase can also metabolise androstenodione to produce oestrogen sulphate (circulates in plasma)
What are the types of aromatase inhibitors?
Suicide inhibitors e.g Exemestane
- Competitive with androstenedione and testosterone for binding to aromatase
- Enzyme acts on the inhibitor to create reactive alkylating species which covalently bond the active site of the enzyme -> irreversibly inactivated
Competitive inhibitors e.g Anastrozole
- Binds irreversibly to aromatase
What are the uses of progestins?
- Endocrine treatment of uterine and breast cancers with proven antineoplastic properties
- Metastatic breast cancer as a 2nd or 3rd line therapy (e.g. Megetrol acetate)
How do you combat resistance to endocrine therapy?
As the patients become resistant to endocrine therapy (anti-oestrogens (tamoxifen) and inhibitors of oestrogen synthesis (Exemestane)), the solution is to CONTINUE this therapy and add:
- Additional inhibitors of oestrogen action
