Breast cancer Flashcards
What is breast cancer?
Breast cancer is a disease in which cells in the breast grow out of control.
There are different kinds of breast cancer.
The kind of breast cancer depends on which cells in the breast turn into cancer.
Breast cancer can begin in different parts of the breast.
What are the 3 types of oestrogen?
Estrone (E1) is produced from Estradiol in the liver
and the small intestines.
Estradiol (E2) is synthesised in relatively large
amounts in the ovaries (urogenital tract) & the female
breast. Small amounts in the brain, cardiovascular
system, bone, gastrointestinal tract, liver.
Estriol (E3) is the shortest-acting oestrogen and has
the weakest effect on the oestrogen receptor.
Rank order of potency at the receptor:
estradiol > estrone > estriol
What are the 2 oestrogen receptor subtypes?
ER alpha and ER beta.
ER alpha is involved in breast cancer.
The receptors contain 3 types of domains:
Transcription activation domains (TAD) x 2 that can bind
to the basic transcriptional machinery via co-activator
proteins to stimulate transcription.
DNA binding domain.
Hormone binding domain.
What is oestrogen?
Oestrogen is a transcriptional activator, it stimulates entry into the cell cycle from G0.
The oestrogen receptor is present in the urogenital tract (cervix/uterus/ovaries), breast, brain, cardiovascular system, bone, gastrointestinal tract, liver.
In men it plays a role in spermatogenesis, sexual maturation, cholesterol metabolism and bone strength.
High levels in females from puberty to menopause.
Stimulates growth of the endometrium.
Reduces bone resorption and increase bone formation.
Increases HDL cholesterol and reduce LDL.
Is elevates mood, low levels of oestrogen are associated with depression in women.
What are three different types of antihormonal therapy?
Selective oestrogen receptor modulators e.g. tamoxifen.
Aromatase inhibitors e.g. anastrozole.
Oestrogen receptor downregulators / antagonist e.g. fulvestrant.
What is tamoxifen?
A selective oestrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men.
It is activated by CYP metabolism.
What is the mechanism of action of tamoxifen?
Tamoxifen and its metabolite bind to the breast oestrogen receptor (ER alpha).
Permits the AF1 transcription activation domain to bind to the basic transcriptional machinery via adaptor (co-activator) proteins.
Prevents the AF2 transcription activation domain from binding to the basic transcriptional machinery via adaptor (co-activator) proteins.
This maintains some of the functions of oestrogen via AF1 binding.
eg. enables bone cell division (It does not cause bone destruction as an oestrogen receptors antagonists would).
What are the adverse effects of tamoxifen?
Tamoxifen also binds to the ERβ receptor and acts as an agonist enabling both AF1 and AF2 binding to adaptor proteins leading to increased gene expression.
Results in:
Hot flushes, fluid retention and menstrual irregularities.
Risk of:
Endometrial cancer (due to uterine cell proliferation).
Deep vein thrombosis.
Stroke.
What is anastrozole?
It is an aromatase inhibitor.
Aromatase (CYP19A1) catalyses the synthesis of estradiol from testosterone (the main source of oestrogen in post menopausal women).
Aromatase inhibitors block the synthesis of all
oestrogens from testosterone.
Anastrozole is a reversible inhibitor of CYP19A1.
Blocks oestrogen dependant cell division.
ADRs associated with low oestrogen i.e. menopausal
symptoms.
Decreased risk of endometrial cancer, thrombosis
and stroke.
What is fulvestrant?
It is an oestrogen receptor antagonist.
This binds to the receptor resulting in receptor downregulation and antagonises the ability of the receptor to bind to DNA.
May also inhibit aromatase.
No beneficial oestrogenic effects.
Similar adverse effects to tamoxifen.
What is HER2 positive breast cancer?
HER2 positive breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2). This protein promotes the growth of cancer cells.
What medications are used to treat HER2 positive breast cancer?
Trastuzumab:
Prevents HER2 homodimer formation.
It can be conjugated with mertansine (a microtubule inhibitor).
Pertuzumab:
Prevents HER2 heterodimer formation with HER3.
Chemotherapy may also be used.
What are BRCA1 and BRCA2?
BRCA1 and BRCA2 are tumour suppressor genes.
Mutation in both copies of the gene is required for inactivity, mutation is the second copy is normally acquired by a somatic mutation.
BRCA1:
Involved in double strand break repair.
Increases risk of breast cancer and ovarian cancer.
Increase risk of prostate cancer.
BRCA2:
Involved in homologous recombination.
Increased risk of gall bladder, bile duct, stomach cancer and melanoma.
What medications are used to treat BRCA breast cancer?
Treated with cytotoxic combination chemotherapy:
Fluorouracil (anti-metabolite).
Epirubicin (topoisomerase inhibitor).
Cyclophosphamide (DNA crosslinker).
Docetaxel (microtubule inhibitor).
Advanced cancer treated with a PARP inhibitor and
chemotherapy.
