Cancer 12: Flashcards
what are the major statistics of breast cancer?
- Breast cancer is the leading female cancer, accounting for almost 1 in 5 cancer deaths among women.
- 1 in 8 women in the UK and the USA will develop the disease in their lifetime
- Currently, around 55,000 women develop breast cancer every year in the UK.
- breast cancer incidence has been increasing each year
- breast cancer mortality has been falling each year
why has the mortality of breast cancer decreased?
- chemo and radiotherapies are much better
- earlier diagnosis due to public health message to women to check their breasts
what is special about the breast organ?
- This is the only organ that develops after birth
- During puberty the breast develops into a fatty glandular structure
what is the structure of the breast?
- there is a tubular network of ducts and glands within the breast which comes together at the nipple
what is the phyllodes tumour?
this is a tumor in the fatty stromal area it is a very rare and very aggressive type of tumor
where does the majority of breast cancer originate from?
- The majority of breast cancer (>90%) originates in the luminal epithelium
what is the cellular organization of the mammary gland?
how many layers of epithelial cells?
- Between the tubules, you have fatty stromal cells
- there are two layers of epithelial cells
luminal epithelial cells
myoepithelial cells (surround the luminal cells)
what do the Myoepithelial cells do?
- the myoepithelial cells have a contractile phenotype
- they contract when they receive the correct hormonal signals
- they need to contract so they can force the milk out of the breast
why are myoepithelial cells important?
- Myoepithelial cells are very important in the development of the gland
- They are responsible for the formation of the tubules
- the luminal cells lie passively underneath
what do the luminal epithelial cells do?
- some of the luminal epithelial cells express estrogen receptors (10%-15%)
how do the cells in the breast respond to estrogen?
- in a normal gland the response to estrogen is to stimulate growth
- the oestrogen receptor positive cells do not grow in repsonse to oestrogen
- instead the oestrogen receptor-positive cells produce growth factors that stimulate the growth of nearby cells
what happens to the oestrogen receptor cells in breast cancer?
- the oestrogen receptor cells directly respond to their own signal and stimulate their own growth
what is a precancerous state of the breast cells?
- when there is a proliferation of the luminal cells but the myoepithelium is still around it
what is a lobular carcinoma?
- produce growth factors that stimulate the growth of nearby cells
what is a medullary carcinoma?
- the tumor cells don’t look anything like the epithelial cells from the mammary gland
what are the majority of breast cancers?
- they are nt medullary or lobular they are just breast carcinoma
what is a main histological test carried out on breast tumors?
- stsaining of the tissue samples for the oestrogen receptor is carried out to classify the breast tumors as
- ER-positive
- ER-negative
what is being stained in the test for estrogen receptors ?
- It is the nuclei that are being stained in this test because ER is a transcription factor that is found in the nucleus
what percentage is a positive ER?
80%
what are some risk factors for ER positive breast carcinoma ?
- Early age of onset of menstruation
- Late age to menopause
- Age to first full=term pregnancy
- Some contraceptive pills
- Some HRTs
how does the oestrogen bind to the ER receptor?
what are the effects?
- ER is a cytosolic receptor = inside the cell
- it is bound to a heat-shock protein forming a dimer
- estrogen is very lipophilic and ca pass through the cell membrane
- once inside the cell the estrogen binds to the ER and displaces the heat shock protein
- Two oestrogen receptors then come together to form a dimer, this dimerised protein enters the nucleus and locate DNA sequences in the genome that are response elements for this transcription factor
- the most important target genes of the transcription factor are the following:
Progesterone receptor
Cyclin D1
C - Myc
TGF alpha
- the oestrogen induced gene products result in increased cell proliferation resulting in breast cancer
why is the dimerisation of the ER significant?
- the response elements are present in two halves so each half of the dimer will bind to each half of the response element
how are pre menopausal women with breast cancer treated?
- About 1/3 of PREmenopausal women with advanced breast cancer will respond to oophorectomy
- this is removal of the ovaries
how are post-menopausal women treated?
- breast cancer in post-menopausal women responds to high dose therapy with synthetic estrogens this causes breast tumor regression
- if you overstimulate this hormone system it will result in the downregulation of ER so the cells are no longer responsive to estrogen
how common is ER overexpression?
what does the presence of ER suggest?
- ER is overexpressed in 70% of breast cancers
- Presence of ER is indicative of a BETTER PROGNOSIS
what does an increased level of expression of ER in men suggest?
- good prognosis in women
- worse prognosis in men
what are the three types of endocrine therapy used in breast cancer?
- Ovarian suppression
- Blocking oestrogen production by enzymatic inhibition
- Inhibiting oestrogen responses
where is oestrogen made for pre-menopausal women?
where is oestrogen made for post menopausal women?
- pre-menopausal women = ovaries
- post-menopausal women = aromatisation of androgens in peripheral tissues (fat)
what is the function of Ovarian Ablation?
how is it carried out?
Aims to eliminate this source of estrogen
- Surgical oophorectomy
- Ovarian irradiation
what are the major problems with ovarian ablation?
- Results in morbidity and irreversibility so one cannot have children
what is medical ovarian ablation?
- in order to overcome the problems of ovarian ablation
- medical ovarian ablation achieves reversible effects using luteinizing hormone-releasing hormone (LHRH) agonists
- LHRH agonists bind to LHRH receptors in the pituitary leading to receptor downregulation and suppression of LH
- this results in inhibition of ovarian function including estrogen production
examples of LHRH agonists?
- goserelin
- buserelin
- triptorelin
- leuprolide
what is the action of anti oestrogens such as tamoxifen?
- Tamoxifen is an ER receptor blocker (competitive inhibitor)
- Tamoxifen negates the stimulatory effects of estrogen so prevents the cells proliferating
what is the most common side effect of Tamoxifen?
- hot flushes
what is Tamoxifens other feature?
Tamoxifen is a SERM (selective oestrogen receptor modulator)
- this means although Tamoxifen blocks estrogen it still allows the beneficial effects :
- Tamoxifen is oestrogenic in bone, protects against osteoporosis
- Tamoxifen is oestrogenic on the cardiovascular system so decreases atherosclerosis risk
what is a negative side effect of tamoxifen?
- increases the risk of thromboembolic events
- it can cause endometrial hyperplasia (increases risk of endometrial cancer)
what is Faslodex?
advantages over tamoxifen?
- shows no estrogen-like activity in laboratory tests
- but effective in controlling oestrogen-stimulated growth
- Faslodex is a pure anti-oestrogen
- Faslodex offers advantages over tamoxifen by decreasing tumour cell invasion and the stimulation of occult endometrial carcinoma
what is Raloxifene?
- It is an agonist in bone but has no activity in the breast or uterus
- It is used in the treatment of osteoporosis in post-menopausal women
how might tamoxifen be used for preventative measures?
- tamoxifen reduces contralateral breast cancer by a third
- this has lead to trials of tamoxifen being able to prevent breast cancer
- the trials have focussed on treating high-risk patients
what are the major problems with using Tamoxifen in prevention?
- Endometrial cancer
- Stroke
- DVT
- Cataracts
To overcome these problems, prevention trials are being conducted with:
Raloxifene/Faslodex (SERMs)
Aromatase inhibitors
in postmenopausal women what is the major source of estrogen?
- the major source of oestrogen derives not from the ovaries but from the conversion of the adrenal hormones to oestrone
- this conversion occurs at peripheral sites such as fat, liver and muscle
- The conversion is catalysed by the aromatase enzyme complex
what does the aromatase complex consist of?
- CYP450 heme-containing protein
- NADPH CYP450 reductase
what are the two types of aromatase Inhibitors in Breast Cancer?
- Suicide Inhibitors
- Competitive Inhibitors
how do suicide inhibitors work?
- compete with the natural substrate for binding to the 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
- this means that the enzyme is irreversibly inactivated
example of suicide inhibitor?
side effects?
- Exemestane
- mild side effects including : hot flushes, nausea, fatigue
how do competitive inhibitors work?
- binds reversibly to the active site of the enzyme and prevent product formation only as long as the inhibitor occupies the catalytic site
example of competitive inhibitor?
- Anastrozole
how are progestins used in the treatment of breast cancer?
- Progestins are used in the endocrine treatment of uterine and breast cancer
- it has anti-neoplastic properties
- progestin therapy for metastatic breast cancer is the second or third like therapy
- the main progestin is megestrol acetate
what is a major issue with endocrine therapies?
- a significant proportion of patients presenting with breast cancer become resistant to endocrine therapies
- ALL patients with metastatic disease become resistant to endocrine therapies
how is screening for breast cancer carried out?
*
show a basic patient history of breast cancer ?
