Breast cancer Flashcards
Estrogen receptor
- activated upon binding estrogen
- gene expression induced by binding to Specific DNA Sequences called Estrogen Response Elements
- Estrogen-induced gene products increase cell proliferation, resulting in breast cancer
Important estrogen regulated genes
- Progesterone receptor
- Cyclin D1
- c-myc
- TGF-alpha
Major treatment approaches for breast cancer
- Surgery
- Radiation therapy
- Chemotherapy
- Endocrine therapy
Endocrine therapy
- cornerstone of breast cancer treatment
- therapy results in ovarian suppression, blocking estrogen production by enzymatic inhibition and inhibiting estrogen responses
Hormonal control of target tissues
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What is the major source of estrogen biosynthesis in pre-menopausal women?
Ovaries
Ovarian ablation
Carried out by:
- Surgical oophorectomy
- Ovarian irradiation
-major problems with these procedures are morbidity and irreversibility=overcome by designing treatments to produce medical ovarian ablation
LHRH agonists
- Luteinising Hormone Releasing Hormone agonists
- reversible and reliable medical ovarian ablation
- bind to LHRH receptors in pituitary leading to receptor down-regulation and LH release suppression and ovarian function inhibition (including estrogen production)
- examples include Goserelin, Buserelin, Leuprolide and Triptorelin
Aromatase inhibitor target sites
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LHRH agonist target site
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Antiestrogens target site
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Breast cancer risk factors
- early age of onset of menarche (first occurrence of menstruation)
- late age of menopause
- age at first full-term pregnancy
- some forms of contraceptive pill
- Hormone Replacement Therapy (HRT)
- Obesity
- Diet, physical activity, height, medication (aspirin)
Breast cancer screening
- mammography to screen all women 50-64 years old who are registered with a GP in the UK
- screening age being extended to 70 years old across the country
- each patient asked to attend test once every 3 years
- > 70% of women attend breast screening appointments=more than 1,200,000 women screened for breast cancer each year
- only 6/100 are asked to go back for more tests
- > 90% of breast tumours are first spotted by women themselves
Patient history of breast cancer
1) lump detected (self examination/GP)
2) referred to hospital
3) examined by surgical team (mammogram, FNA)
4) surgery performed (lumpectomy/mastectomy)
5) tumour examined pathologically (ER/PR)
6) see physician for first time
Problems with using Tamoxifen in breast cancer prevention
- increase incidence of endometrial cancer
- stroke
- deep vein thrombosis
- cataracts
Overcoming problems with Tamoxifen
Prevention trials are being conducted with:
- Raloxifene/ Faslodex (SERM)
- Aromatase inhibitors
Aromatase inhibitors
- in postmenopausal women, the major source of estrogen derives not from ovaries but from enzymatic conversion of adrenal hormones Androstenedione (A) and to a lesser extent, Testosterone, to Estrogen=occurs at extra-adrenal or peripheral sites (fat, liver and muscle)
- enzymatic conversion catalysed by aromatase enzyme complex
Aromatase
- consists of a complex containing a cytochrome P450 heme containing protein and the flavoprotein NADPH cytochrome P450 reductase
- catalyses 3 separate steroid hydroxylations involved in androstenedione conversion to estrone
- aromatase can metabolise androstenedione (produced by adrenal glands)=leads to estrone sulphate production which is circulated in plasma
Type I aromatase inhibitors
-mechanism-based/suicide
Type II aromatase inhibitors
-competitive
Progestins in breast cancer
- progesterone is the dominant naturally occurring progestin
- poor absorption of progesterone=overcome with some synthetic derivative progestins
- progestin response in the human breast=complex and influences both proliferation and differentiated function
- progestins used in endocrine treatment of uterine and breast cancer with clinically proven antineoplastic properties
- progestin therapy for metastatic breast cancer=used principally as second or third line therapy following selective estrogen
- principal progestin used for metastatic breast cancer has been megestrol acetate
Estrogen receptors in breast cancer
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Estrogens and anti-estrogens
- Tamoxifen=competitive inhibitor of estradiol binding to ER
- antiestrogens negate stimulatory effects of estrogen=block ER causing cell to be held at G1 phase of cell cycle
- Tamoxifen=endocrine treatment of choice for metastatic disease in postmenopausal patients (~1/3 patients respond)
- few side effects reported=hot flushes (29% reported) most commonly reported during Tamoxifen therapy
Tamoxifen
- Selective estrogen receptor modulators (SERMs)
- estrogenic effects in bone
- estrogenic effects in the cardiovascular system
- Anecdotal reports associating the administration of Tamoxifen for advanced breast cancer with subsequent thromboembolic episodes
- Tamoxifen is known to produce endometrial thickening, hyperplasia and fibroids following several years of therapy
Estrogen desirable effects
- improves cognitive function (brain)
- programs glands to produce milk (breast)
- lowers cholesterol, reduces atherosclerosis and heart attacks (liver and heart)
- programs uterus to nourish a foetus (uterus)
- maintains density to help prevent bone loss (bone)
Estrogen negative effects
- promotes breast cancer (estrogen)
- increases thromboembolism (liver)
- promotes endometrial cancer (uterus)
Tamoxifen desirable effects
- reduces breast cancer (breast)
- lowers cholesterol, reduces atherosclerosis and heart attacks (liver and heart)
- maintains density to help prevent bone loss (bone)
Tamoxifen negative effects
- increases vasomotor symptoms (hypothalamus)
- increases cataracts (eye)
- increases thromboembolism (liver)
- promotes endometrial cancer, fibroids, polyps and vaginal discharge (uterus)
