Introduction To Hormone Dependent Cancers: Brest And Prostate Cancer Flashcards
1
Q
What is a hormone?
A
Chemical messenger made by specialist cells (endocrine glands) released into bloodstream to have effect on another part of the body
2
Q
Where are hormones produced?
A
Endorcrine glands
- ovaries, uterus
- testes
- hypothalamus
- pituitary gland
- thyroid
- thymus
- pancrease
- adrenal cortex
- kidneys
3
Q
What are the 3 main classes of hormones? and example of each
A
Steroids - lipid soluble e.g. testosterone
Peptide/protein e.g. insulin
Modified amino acids/amine hormone e.g. adrenaline
4
Q
What are steroid hormones synthesis from?
A
Cholesterol
5
Q
What is the structure of steroid hormones?
A
4 ring steroid backbone structure + lipophilic so can pass through membranes
6
Q
Where does cholestrol comes from?
A
Ingested or synthesised de novo in body
7
Q
How are steroids synthesised breifly?
A
Cholestrol converted to corticosteroids/mineralocorticoids in adrenal cortex
Androgenic / estrogenic precursors secreted into blood and reach gonadal tissues
Androgens and estrogens product in gondal target tissues and released into blood stream
8
Q
name a few steroid hormones
A
Androgen (testosterone) Estrogen (estrodiol) Progestogen (progesterone) Corticosteroid (cortisol) Minerlocorticoid (aldosterone)
9
Q
What are the sex steroid hormones?
A
Hormones made by gonadal tissues
10
Q
What is the purpose of sex steroid hormones?
A
sexual dimorphism between males and females
- development of secondary sexual characteristics
11
Q
What are the effects of estrogen in females?
A
Control menstural cycles, breast tissue development, fertility, reproductive organ development, secondary sexual characteristics e.g. body hair
12
Q
What are the effects of testosterone in males?
A
Reproductuve and supportive organ(prostate) controls
development of sexual characterisitics (e..g deepening of voice and body hair)
13
Q
What is the link between breats/prostate cancer and sex steroid hormones?
A
Sex steroid hormones strongly control breast and prostate tissue growth ad development
14
Q
What do steroids control i breast and prostates?
A
Cellular prolideration, tissue function, gene expression and morphology of tissues
15
Q
What do steroids control in cancers of breast and prostate
A
Steroid hormones still influence cells grwoth and function casuing disease to develop and progress
16
Q
What is the action of steroid hormones? receptor mechanisms of action
A
Steroids circulating in blood enter cell due to lipphilic nature across membrane + bind to nuclear receptors found in the cytoplasm or nucleus
Nuclear receptor releases chaperone proteins after confirmational shape change of steroid binding to it and translocates to nucleus
In nucleus, steroid receptor binds to DNA specificic sequences in the promoter regions of steroid response elements
Steroid receptirs recruit transcription factors and coactivators to induce gene expression
17
Q
What are the key characteristics of the nuclear receptor?
A
Ligand binding domain (binds to specific steroid hormone)
DNA binding domain - binds to specific dna sequences in the response element
Activation function domain (AF1 and AF2)
- recruits activation machinery for gene expression
18
Q
Why are nuclear receptors called ligand activated receptors?
A
Steroid hormone must bind to be activated
19
Q
What happens to nuclear receptors when ligans (steroid) binds to ligand binding site?
A
Physical confirmation shape change of polypeptide chains (ALPHA HELIX domains) in receptor to activate the receptor
20
Q
What happens once steroid binds to nuclear receptor and translocates to nucleus?
A
Shift in alpha helix due to ligand binding causes receptor to be activated
Activated receptor dimerises and moves to nucleus and binds to specific DNA sequences
Receptor recruits DNA modifiying enzymes and transcription factors to promoter hormone responsive genes activation
21
Q
What is the structure of the DNA binding domain on the nuclear receptor?
A
2 zinc finger domains essential for binding to specific DNA sequences
22
Q
Why are the zinc figer domains important?
A
To bind to specific DNA sequences in steroid responsive genes
- they
23
Q
How are genes affected from steroid hormones?
A
Genes are upregulated and some are downregulated
24
Q
What types of genes are affected by steroid hormones?
A
Tissue specific genes, cell cycle and proliferation genes, and genes involved in tissue development and differentiation
25
What are hormone responsive elements?
Specific DNA sequences found in the promoters of hormone responsive genes
26
Where do the nuclear recepotrs binds on dna?
Hormone response elements
27
What is the structure of the hormone response element?
Palindromic
| 6 bases separated by 3 spacer DNA bases and another 6 dna bases that is a palindromic repeat
28
What do all nuclear receptors share?
Common domain structure from common evolutionary ancestor
| - distant evolutionary ancestors may bind to other things instead of steroids e.g. fatty acids, bioacids, precursors
29
What are the abbreviattion for main steroid receptors? and their ligands
ER - estrogen receptor - ligand for estrodiol, estriol
AR - androgen receptor - ligand is androgens (testosterone)
PR - progesterone receptor - ligand is progesterone
GR - glucocorticoid receptor - ligand is cortisol
MR - mineralocorticoid receptor - ligand is aldosterone
30
What are the main sex hormone receptors for each type of cancer?
ER and PR for breast cancer
| AR for prostate cancer
31
What type of gland is the breast?
Apocrine gland
32
What is the breast made up off? (structur of breast)
Glands(lobules produce breast milk) and ducts(carry the milk)
33
What is an exocrine gland?
Secrete substances out onto a surface or cavity via ductal surface
34
What is an endocrine gland?
Secrete substances directly into the bloodstream
35
What is an apocrine gland?
Specialised exocrine gland in which a part of cell's cytoplasm breaks off releasing the contents
36
What is the structure of mammary gland tissue?
2 cel compartments
| - Luminal and basal
37
What is the luminal cell compartment? + its function it mammary gland tissue
Single layer of polarised epithelium around the ductal lumen, luminal cells produce milk during lactation
38
What is the basal cell compartment and its function if mammary gland tissue?
Cells that don't touch the lumen
Myoepithelial cells in contact with basement membrane
Function - contractile function during lactation to move milk into the ducts
39
What are the 2 phases of mammary gland development?
Hormone independent from embryonic development to puberty
Hormone dependent after puberty, menstrual cycle and pregnancy
40
Which effect does estrogen and other growth hormones have on breasts?
Drive the expression of genes involved in cellular proliferation and differentiation of the breast - MAINLY IN INITIAL GROWTH OF BREAST
Causes ductal elongation and triggers side branching after puberty (hormone dependent stage of mammary gland development)
As adult, maintains mammary gland tissue
41
What other hormones are involved in breast development?
Cortisol, growth hormones
42
What effect does progesterone normally have on the mammary glands?
MAIN FUNCTION IS TO INCREASE BRANCHING OF DUCTS
43
What effect does progesterone have on breats during pregnancy and why?
During pregnancy, progesterone levels increases causing prolonged progesterone receptor activity leading to more side branching and lactogenic differentiation (for milk production) together with PROLACTIN HORMONE
44
What activates progesterone receptor gene?
Progesterone receptor gene swtiched on by estrogen receptor
45
Which hormones are involved in lactogenic differenitation during pregnancy?
prolactin and progesterone(more so in side branching)
46
Where does breast cancer commonly start?
Cells that line milk ducts within breast tissue
47
How does age affect breast cancer?
Increased risk
48
Which gene mutations contribute to breast cancer risk?
BRCA1 and BRCA2
| - inherited = higher risk of breast and ovarian cancer
49
What are some risks for breast cancer?
Age
genetic mutations
Reproductive history (early onset of menstrual cycle or late menopause - prolonged hormone exposure)
Overweight/obese
Hormone replacement (birth control pills)
Late pregnancy/not breastfeeding
50
What is DCIS?
Ductal breast carcinoma in situ
| - cancer develops in ducts and havent spread outside of ducts into breast tissue
51
What is LCIS?
Lobular carcinoma in situ
| - abnormal cells found in milk glands (lobules)
52
Is DCIS or LCIS isn't cancer and why?
LCIS isnt cancer, only indicates increased risk of developing breast cancer
53
What are lobules?
Milk producing glands in the breast
54
Wha are ducts?
Tubes that carry milk from the lobules that produce the milk to the nipple
55
What surrounds lobules and ducts inbreasts?
Glandular, fibrous and fatty tissue
56
Which cell compartment do most breast cancers arise from? and why?
Luminal cells because they express estrogen receptors
57
What is the prognosis of estrogen receptor expression and types of tumours in breasts?
```
Luminal cells (express ER) better prognosis
Basal cells (do not express ER - ER-ve) worse prognosis
```
58
Why do breast cancers that arise from basal cells have a worse prognosis?
ER -ve cells cannot be treated hormonally and need more conventional therapies
59
What are the different subtypes of breast cancer?
Many subtypes apart from Er+ve or ER-ve
best to classify simply as either ER+ve or PR+ve
60
What is progesterone receptor indicative of?
estrogen activity
61
Why does ER result in breast cancer?
Normally controls cell functions e.g. cell proliferation, development and differentiation in controlled manner
ER signalling pathway becomes uncontrolled in breast cancer resulting in transcription of many genes
62
What is the achilles heel of breast cancer?
Switch of ER signalling will switch off cancer growth
| - since breast is sensitive and dependent on estrogen
63
What does the cross section of breast tissues look normally compared to in breast cancer?
Normal, ER stained, can see ER+ve cells lining ducts
| In cancer ER stained, ER+ve cells fill entier lumen and invade outside lumen showing tissue breakdown
64
What is estrogen action causing breast cancer? (step by step)
Estrogen binds to estrogen receptor at ligand binding site causing estrogne receptors to dimerise and translocate to nuclues. Dimerised estrogen reveptor binds to DNA activating AF1 and AF2. This recruits transcriptional proteins and coactivators for full gene transcription - breast cancer growth
65
What are the drugs that are used against breast cancer?
Fulvestrant (faslodex)
Tamoxifen
Aromatase
66
What is the point of inhibiting estrogen action with drugs?
Block estrogen binding to receptor degrades the ER protein. No ER means no ER signalling preventing breast cancer cell growth
67
What is fulvestrant?
Analogue of estradiol - competitively inhibits estradiol from to the ER
68
What happens when fulvestrant binds to ER competitively?
ER binding to fulvestrant causes impaired ER dimerisation (fulvestrant has long arm preventing the dimerisation) which prevent energy dependent nucleo-cytoplasmic shuttling.
If any fulvestrant-ER comlex enters nucleus, AF1 and AF2 are disabled
Fulvestrant-ER complex is also unstable so ER degradation is accelerated
69
What is tamoxifen?
SELECTIVE ESTROGEN RECEPTOR MODULATOR (SERM)
Partial agonist for ER - doesn't fully activate ER
Activates ER in uterus and liver but acts as an ANTAGONIST in breast tissue
70
Where does Tamoxifen bind on ER?
Ligand binding site
71
What happens when Tamoxifen binds to ER?
ER cannot fold properly (only some confirmational shape change) so AF2 domains don't function so only AF1 is active so only some coactivator are recruited causing partially inactivated transcription of gene
- only in breast not liver (other cofactors present there for full activation)
72
Where does estrogen come from in postmenopausal women?
Peripheral conversioj of androgens by aromatase enzyme
73
Where is aromatase enzyme found?
Multiple organs including breast tissue, adipose tissue, brain, blood vessels, skin, bone and endometrium
74
What is the aromatase inhibitor mechanism?
Prevents conversion of ketone group
75
What are the types of aromatase inhibitors?
Type 1 inhibitors
| Type 2 inhibitor
76
Give example of aromatase type 1 inhibitors and their mechanism of action
Exemestane - androgen analogues that bind irreversably to aromatase
77
Give example of aromatase type 2 inhibitors
Anastrozole
78
When may conventional chemotherapy be used against breast cancer?
Some may develop resistance to anti-estrogen therapy and relapse so need chemotherapy
79
What is the function of prostate\'
Produce prostatic fluid that creates semen when mixed with sperm created by testes
80
What type of gland is prostate?
Exocrine - specifically apocrine
81
What are the stages of normal prostate development?
Hormone independent from embryonic stage to puberty
Enlargement during puberty
Hormone dependent maintenance after in adulthood
82
Why does cancer develop in testes?
- reactivation of prostate growth in old age leads to hyperplasia and cancer
83
What are development prostate abnormalities and examples of conditions for both
- inflammation e.g. prostatitis - linked to infertility
| - dysregulated growth of prostate - benign prostatic hyperplasia (BPH) or malignant prostate cancer
84
What are some symptoms of prostate cancer? and what is it caused by?
```
Frequent trips to urinate
Poor urinary system
Urgency to urinate
Lower back pain
Blood in urine
```
Cancer applied pressure on bladder and compresses urethra
85
Where does prostate cancer start?
Luminal epithelial cells
86
What are the steps in prostate cancer development?
Normal prostate epithelium luminal cells hyperproliferate forming prostatic intraepithelial neoplasia (PIN)
Continue hyperproliferation fills lumen and progresses outwards forming invasive adenocarcinoma
87
How do we detect prostate cancer?
1) Digitial rectal examination (for lumps)
2) PSA test (antibody based test of prostate antigen that escapes into blood due to damaged prostate)
3) Ultrasound - detect tumour
88
What has to be done after diagnosis of prostate cancer?
Prostate cancer staging using TNM system using biopsy of tumour
89
What are the T stages of TNM stages of prostate cancer?
T1 - small localised tumour
T2 - Palpable tumour
T3 - escape from prostate gland
T4 - local spread to pelvic region
90
What are the N stages of TNM stages of prostate cancer?
N0 - N0 cancer cells found in any lymph nodes
N1 - 1 positive lymph node less then 2cm across
N2 - >1 positive lymph node or 1 between 2-5cm across
N3 - any positive lymph node over 5cm
91
What are the M stages of TNM stages of prostate cancer?
M1a - non-regional lymph nodes
M1b - Bone
M1c - Other sites
92
How can prostate cancer be graded by pathology?
Normal prostate - clear ordered structure
Hyperplasia - structure closing in
High grade - no differentiation, no lumen
93
What is the grading system for prostate biopsy samples
Gleason's patter
| - higher gleason score = more aggressive and less differentiated so worse prognosis
94
What are the prostate cancer treatment options
Watchful waiting - low grade tumour
Radical prostatectomy - Stage T1 or T2
Radical radiotherapy - External up to T3
Hormone therapy - with or without prostatectomy and radiotherapy, with metastatic prostate cancer
95
How can risk factors for prostate cancer cahnged??
Exposure/non inheritable - can be changed
| Heritable cannot changed
96
What are the different risk factors specific for prostate cancer?
Age - older
Race ethnicity - african american
Family history
Gene changes/inherited - BRCA1 and BRCA2 mutated gene, Lynch syndrome
97
What are some general risk factors for prostate cancer?
Diet, obesity, chemical exposure, inflammation of prostate (prostatitis), sexually transmitted infections e.g. HPV
98
What are the prostate cancer gene mutations?
BRCA1 mutations and PTen loss
| TMPRSS@-ERG fusion
99
What is PTen
Phosphotase that antagonises phosphotidylinositol 3 kinase signalling pathway
100
What happens if Pten is lost?
Increase in growth factor signalling because Pten counteracts growth signalling pathways
Leads to inappopraite cell growth and proliferation
101
What is TMPRSS2
Gene thats driven by androgen receptor transcription factor
102
What is ERG?
proto-oncogene?
103
What happens when TMPRSS2 and ER fuses?
Promoter and proto-oncogene fusion = Strong proliferation signal due to testosterone
104
What other generic mutations occur ac prostate cancer develops?
p%£ and Kras
105
What does the growth and development of prostate depend on?
Presence of androgens
| - esp testosterone
106
Where is testosterone produced?
Testes
107
What are the steps of androgen receptor (AR) signalling? all steps
1) Androgen receptor is a nuclear receptor and testosterone circulates in cytoplasm then moved (passes through cell membrane since it's lipophilic) into prostate.
2) Ligand binding and dimerisation (testosterone converted to DHT in prostate by 5 alpha reductase - DHT binds to AR with high affinity causing activation and dimerisation of AR)
3) DNA binding and coactivator recruitment - Androgen receptor and DHT complex translocates to nucleus where it binds to androgen response elements and recruits transcription factors and coactivators for transcription of target gene
4) Target gene causes cell growth - cancer arises
108
Why are androgen receptors targetted in prostate cancer?
Prostate gland is androgen sensitive and dependent and androgens drive prostate cancer growth.
Inhibiting AR switches of cancer growth (Achilles heel)
109
What are the steps for testosterone production?
Cholesterol (precursor) in adrenal glands circulate blood and reach testes and converted to testosterone
Testosterone circulates and reached prostate where its converted to DHT which binds to AR and androgen receptor signalling mechanisms occurs
110
Which stages of testosterone production and AR signalling can be targetted for inhibition in cancer?
Inhibit testosterone synthesis !!!
Inhibit testosterone conversion to DHT
Inhibit androgen (DHT) binding to receptor (AR)
111
How can we inhibit testosterone synthesis?
Abiraterone or abiraterone acetate inhibits the enzymes required to convert cholestrol to andrenal androgens
112
How are androgen produced due to HPG axis?
GNRH release by Hyp which travels to ant pit via portal vein and stimulates fsh and lh production.
FSH and LH in circulation reach testes where it stimulates testosterone production
113
Why can we target HPG axis as well to inhibit tesosterone production?
HYP sensitive to circulating testosterone levels and high reduced GnRH levels and vice versa due to negative feedback loop
- targetting this can change levels of testosterone made
114
What drugs are used to target HPG axis to inhibit testosterone synthesis?
Synthetic peptides - GnRH antagonists and super agonists
Gosarelin - super agonist
Abarelix - antagonist
115
How can we inhibit testosterone to DHT conversion to lower testosterone levels? and what conditions is it used in?
5a reductase inhibitor
Benign prostate hyperplasia (BPH)
116
name a few 5a reducatse inhibitors
Finasteride
| Dutasteride (avodart)
117
What is hyperplasia?
Increase in number of cells in organ or tissue
118
What is used to inhibit androgen (DHT) from binding to the androgen receptor (AR)?
Competitive andorgen antagonists - which bind to the AR receptors ligand binding site instead
119
Give drug names of competitive anti-androgens (block androgen from binding to androgen receptor)
Bicalutamide
Enzalutamide
Flutamide
Nilutamide
120
What are the different mechanisms in prostate cancer that allows it to overcome hormonal therapies (lowering hormone levels)? 8 methods
Hormone overproduction/local synthesis
Ligands binding site mutations allow other hormones to binds
Receptor amplification
Receptor phosphorylation causes activation in absence of ligand
Androgen receptor transcript variants causes activation in absence of ligand
Receptor bypass
Receptor cofactor amplification
Antagonists become agonists via LBD mutations
121
How does the body overcome hormonal therapy in breast/prostate cancer using:
Hormone overproduction/local synthesis?
Advanced tumour synthesises own steroid hormones causing autocrine stimulation regardless of circulating steroid hormone levels
122
How does the body overcome hormonal therapy in breast/prostate cancer using:
Ligands binding site mutations allow other hormones to binds
Ligand binding site mutations make it more promiscuous allowing binding of other steroids e.g. cortisol, estrogen still allowing activation of gene and growth of cells
123
How does the body overcome hormonal therapy in breast/prostate cancer using:
Receptor amplification?
More receptors so signal amplification and increased sensitivity to low circulating steroid hormone levels
124
How does the body overcome hormonal therapy in breast/prostate cancer using:
Receptor phosphorylation causes activation in absence of ligand?
Growth factors phosphorylate and activat receptors esp estrogen receptors in breast cancer so receptor activated even when steroid hormone not present
125
How does the body overcome hormonal therapy in breast/prostate cancer using:
androgen receptor transcript variants causes activation in absence of ligand?
AR variant 7 is truncated without terminus C so can be active even without ligand and goes onto bind to target gene
126
How does the body overcome hormonal therapy in breast/prostate cancer using:
Receptor bypass?
Other switches/oncogenes or trancription factors drives the growth forward instead that is indpenedent of steroid hormone levels
127
How does the body overcome hormonal therapy in breast/prostate cancer using:
Receptor cofactor amplification?
Cofactors proteins recruited that amplify signal from steroid receptors and activate target gene in response to low steroid hormone levels
128
How does the body overcome hormonal therapy in breast/prostate cancer using:
antagonist become agonists via LBD mutations?
In prostate cancer only
The antagonists used as hormone therpay to lower steroid hormone levels can become potent activators(agonists) for the mutant androgen receptor
129
What is the structure of a zinc finger domain in the dna binding domain of the nuclear receptor?
4 cysteine residues linked to a single zinc for each finger
