Introduction to Hormone-Dependent Cancers (Breast/Prostate) Flashcards
What are hormones?
Chemical messenger that is made by specialist cells usually within an endocrine gland and it is released into the blood stream to have an effect on another part of the body .
Where are hormones produced ?
Brain:
Pineeal gland , Hypothalamus and Pituitary
Thyroid:
Thryoid and Thymus gland
Abdomine:
Pancreas and Kidney, Adrenal cortex
Testes (Male )
Ovaries/uterus (Female)
How can hormones be classified ?
Steroids-Lipid soluble small molecules (Testosterone)
Peptide/proteins (Insulin)
Modified amino acids/amine hormones (Adrenaline)
What are steroid hormones ?
All steroid hormones are synthesised from cholesterol either ingested or synthesised de novo in the body and have a basic 4-ring structure .
Cholesterol – Adrenal cortex– Gonadal tissues
Outline the process of steroid synthesis
Cholesterol
In the adrenal cortex:
Main corticosteroids and mineralocorticoids synthesised in the adrenal cortex
Androgenic and estrogenic precursors are released into the blood stream (less potent forms of the final hormone)
Gonadal tissues:
Androgens and oestrogen’s produced in target organs e.g. testes and ovaries -then released into the bloodstream
What are some examples of steroid hormones ?
Androgen-Testosterone Estrogen-Estradiol Progestogen -Progesterone Corticosteroid-Cortisol Mineralocorticoid-Aldosterone
What are the sex hormones ?
These are responsible for the sexual dimorphism between males and females.
The development of the secondary sexual characteristics :
- Growth spurt
- Body hair
- Gonadal development
- Voice change
- Breast growth
- Accessory organs in the reproductive organs -prostate in men
How do steroid hormones work ?
They work systemically :
The effects are :
Females-Oestrogen controls the menstrual cycle and breast tissue development, fertility and reproductive organ development , secondary sexual characteristics -body hair
Males -Testosterone controls reproductive and supportive organ (prostate) development of sexual characteristics in men:
deep voice , body hair
What is the steroid hormone mechanism of action ?
These are small multi ringed structures , lipophilic molecules meaning they can easily enter cells by passing through the plasma membrane
Once they enter the cell they bind to nuclear receptors
1.The steroid hormone circulates in the blood then enters the cell and binds to its receptor.
2, It causes a conformational change in the receptor causing it to dissociate from the chaperone proteins and then translocate into the nucleus .
4.In the nucleus, they bind to DNA at specific sequences called steroid response elements which are short sequences of DNA found in the promoter region of steroid responsive genes
5.Steroid receptor then functions as a transcription factor and recruits the genes transcription machinery
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What are the key characteristics of Nuclear receptor ?
Ligand binding domain -LBD
Binds specific steroid molecules with high affinity
DNA binding domain (DBD)
Binds specific DNA sequences
Activation function domain (Af1 and 2)
Recruits gene activation machinery ,some receptors have a secondary AF2 domain towards the C-terminal
The same basic domains and structure are shared with many of the major nuclear recpetors
What happens when receptors bind steroid hormones ?
When these receptors bind steroid hormones they are activated
They are called ligand -activated receptors
-The binding of steroids to ligand binding domain causes a physical restructuring of the polypeptide chains in the receptor activating it
What are ligand activated transcription factors ?
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Outline hormone responsive genes
One receptor can upregulate many genes
Many hundreds of genes may be upregulated by a steroid hormone receptor
Some genes may be down regulated
Genes include functional tissue specific genes , cell cycle and proliferation genes and genes involved in tissue development and differentiation
What are hormone response elements ?
These are specific DNA sequences found in the promoters of hormone responsive genes.
Many of these are palindromic
E.g. Oestrogen response element
Three bases which are separated by spacer DNA elements
What are response elements?
Receptors zinc finger domains help to recognice the sequences
What are the nuclear super family ?
These are 48 nuclear receptor genes in humans
They all share a common domain structure and are thought to arise from a common ancestor
Activated by ligand binding
What are the main steroid receptors / ligands and abbreviations ?
REFER TO SLIDE
What is the breast ?
Check Slide
What are apocrine glands ?
The mammary gland is a specialised type of exocrine gland
These are specialised exocrine glands in which a part of the cells’ cytoplasm breaks off releasing the contents
What is exocrine glands ?
These secrete substances out onto a surface or cavity via a ductal structure
What is an endocrine gland ?
These secrete substances directly into the bloodstream
What are the two types of glands ?
Exocrine-Duct ,lumen cavity or into skin
Endocrine -Into the blood
What is the mammary gland tissue structure ?
The mammary epithelium consists of two cell compartments:
Luminal -form a single layer of polarised epithelium around the ductal lumen , luminal cells produce milk during lactation
Basal-comprise of the cells that do not touch the lumen, basally orientated myoepithelial cells in contact with the basement membrane have contractile function during lactation
What are the two major phases that are distinguished in mammary gland development?
Hormone-independent from embryonic development up to puberty
Hormone-dependent thereafter during puberty, menstrual cycle and pregnancy
What is the function of oestrogen in the normal breast?
Estrogen , drives the expression of genes involved in cellular proliferation +differentiation (+ growth hormone and cortisol)
Hormone dependent mammary gland development occurs after puberty and results in ductal elongation + triggers side branching.
In the adult oestrogen allows the maintenance of mammary gland tissue and also primes the tissue for effects of progesterone during pregnancy-milk production
What is the normal progesterone activity in the normal breast
Oestrogen =primary initial growth of breast cancer
Progesterone receptor gene is switched on by oestrogen receptor.
It increases branching of the ducts
Prolonged activity - leads to more side branching and lactogenic differentiation (prolactin hormone )
Outline the changes in breast tissue by oestrogen +progesterone +prolactin
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What is breast cancer ?
Occurs when abnormal cells in the breast begin to grow and divide in an uncontrolled way and eventually form a tumour
Breast cancer starts in the breast tissue most commonly in the cells which line the milk ducts of the breast
Main risks -age .lifestyle and genetic familial factors
What is the breast cancer aetiology ?
Age - Risk increases with age -mostly after 50 years old
genetic mutations to certain genes -BRCA1 and BRCA2.
Reproductive history -Menstrual cycle before 12 years and menopause post 55 years =more hormones
Previous treatment using radiation therapy to the chest /breast
What is Ductal breast carcinoma in situ (DCIS)
Breasts are made up of lobules (milk -producing glands ) and ducts (tubes that carry milk to the nipple)-surrounded by glandular , fibrous and fatty tissue
Cancer cells devlop within duct -remain within duct
Not spread outside into surrounding tissue
Outline Lobular Breast carcinoma in situ (LCIS)
Uncommon condition in which abnormal cells form in the milk glands in the breast (lobules)
Not cancer but indicates increased risk
Where does majority of breast cancers arise?
Luminal cells which are cells that express ER.
What is Er(positive) and ER(negative)?
The majority of breast cancers are ER (+ve) which means they can be treated hormonally.
ER(-ve) however have a poor prognosis.
How is oestrogen involved in breast cancer
In normal breast ER controls functions such as cell proliferation,development and differentiation in a highly controlled manner.
In breast cancer , ER signalling pathway is subverted and becomes uncontrolled.
ER ability to bind DNA and open chromatin stops working and is used to transcribe many genes , non-coding RNAS and miRNAS
It then governs cancer cell proliferation + controls and influence many hundreds of genes involved in metastasis .invasion +adhesion
How can we target ER in breast cancer and why ?
Mammary gland is ER sensitive +dependent tissue
Breast cancer cells retain this sensitivity and dependency
ER is key driver of breast cancer growth
Switch off ER signalling =switch off the cancer growth
It is the Achilles heel of breast cancer (ER targeting)
How can we inhibit ER signalling ?
Biopsy samples are often analysed for ER expression and 75% of breast cancers are ER +ve
Therefore these women are candidates for specific treatments that block ER activity
How can we stop oestrogen receptor from functioning ?
Oestrogen binds to its receptor at the ligand binding site which causes the receptor to dimerise and translocate into the nucleus where it binds DNA and recruits in proteins for gene transcription.
e.g.co activators ,chromatin remodifiers,RNA polymerase
The full activation of the ER :AF1 and AF2 are activated triggering full gene transcription-Breast cancer growth
How can we inhibit Oestrogen action ?
Pharmaceutically competitively blocking oestrogen binding to receptor -Degrading the ER protein
No ER signalling -no breast cancer cell growth
What is Fulvestrant (Faslodex)?
Fulvestrant is an analogue of oestradiol
It competitively inhibits binding of estardiol to the Oestrogen receptor with a binding affinity that is 89% that of oestradiol
How does Fulvestrant cause Er degradation?
Fulvestrant-ER binding impairs receptor dimerization and energy-dependent nucleo-cytoplasmic shuttling, thereby blocking nuclear localisation of the receptor.
Additionally any fulvestrant-ER complex that enters the nucleus is transcriptionally inactive because both AF1 and Af2 are disabled
The fulvestrant -ER complex is unstable resulting in accelerated degradation of the ER protein
No gene transcription
Outline the mechanism of action of Tamoxifen
Tamoxifen binds to ER at the ligand binding site
tamoxifen is a partial agonist but does not cause the full activation of ER.
Mixed activity-Activates ER in the uterus and liver but acts as antagonist in breats tissue
Selective Estrogen receptor Modulator (SERM)
Tamoxifen bound ER does not fold properly and the AF2 domains do not function
Describe Tamoxifen bound ER
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What happens when Tamoxifen binds to the ER?
It binds to the ligand binding site and causes conformational change
Only one of the activation domains is active (AF1)
ER remains partially active ,stops breast tissue activity
What are aromatase inhibitors?
When ovaries are no longer functional in post menopausal women , potential sources of estrogen come from the peripheral conversion of androgens by the aromatase enzyme.
This enzyme is present in multiple organs including adipose tissue,brain,blood vessels ,skin ,bone and endometrium and breast tissue
Androgens = testosterone ,adrenal androgens and androstenedione
What is the mechanism of aromatase?
Androstenedione +aromatase =estrone
Testosterone +aromatase =estradiol
Aromatic group and alcohol differentiates estrogens and androgens
What are the two types of aromatase inhibitors ?
Type 1: e.g. exemestane are androgen analogues and bind irreversibly to aromatase so they are called suicide inhibitors. Duration of inhibitory effect is dependent on rate of de novo synthesis of aromatase
Type 2: Anastrozole contain a functional group within the ring structure that binds the heme iron of the cytochrome P450,interfering with the hydroxylation reactions.
What is the main function of the prostate ?
The main function of the prostate is to produce prostatic fluid that creates semen when mixed with the sperm produced by the testes
Where is the prostate gland located and what is it made up of ?
It is an exocrine gland ,which is located just underneath the bladder in the abdomen .
Composed of glandular tissue, produce a system of ducts.
Composed of luminal epithelila cells which sit on basal epithelial cells.
What are the phases of developments of a normal prostate ?
Hormone-independent from embryonic development up to puberty
Enlargement during puberty
Hormone dependent maintenance thereafter in adulthood
+reactivation of prostate growth in old age -Hyperplasia and prostate cancer
What are some abnormalities of the prostate ?
Inflammation -due to infection
Prostatitis-Inferility
Dysregulated growth of prostate
benign : Benign prostatic hyperplasia
Malignant: Prostate cancer
What are the symptoms of prostate cancer ?
- Frequent urination
- Poor urinary stream
- Urgent need to urinate
- Hesitancy whilst urinating
- Lower back pain
- Blood in urine
- Compressed urethra
Where does prostate cancer start ?
originate in the cells lining the lumen which is the luminal epithelial cells.
Hyper proliferates following prostatic intraepithelial neoplasia (PIN) become invasive adenocarcinoma and then spread outwards leaving the prostate
How can we detect prostate cancer ?
Digital rectal examination (DRE)
PSA test -blood sample :Antibody based assay
Ultrasound -To detect tumour outside prostate capsule
Describe the process of prostate cancer staging
When it is discovered;
Biopsy is carried out
T1:Small localised tumour
T2:Palpable tumour
T3:Escaped the prostate gland
T4:Local spread to pelvic region
TNM :
T =size (primary tumour)
N=Number of lymph nodes involved
M=Metastasised or not
What is N+ in prostate staging ?
N0= No cancer cells found in lymph nodes
N1+ 1 positive lymph node (<2cm across)
N2= ,1 positive lymph node or 1 between 2-5 cm across
N3=Any positive lymph node . 5 cm across
What is M+ metastatic ?
Has the cancer metastasised and where (PET scan detects this )
M1a =Non regional lymph nodes
M1b=bone
M1c =other sites
How can the biopsy sample of prostate cancer be graded ?
- Normal prostate
- Hyperplasia
- High grade carcinoma
As it progresses there is a loss of glandular structure + irregular structure
What is the Gleason grading system ?outline this
The Gleason grading system =
Helps evaluate prognosis of men using prostate biopsy samples
Samples are examined by clinical histologist
prostate cancer staging predicts prognosis
cancer with higher score =more aggressive and worse prognosis
What are the stages of the Gleason grading system?
1.Small uniform glands (Well differentiated )
2.More stroma between glands
3.Distinctivly infiltrative margins
(Moderately differentiated )
4.Irregular masses of neoplastic glands
(Poorly differentiated /Anaplastic)
5.Only occasional gland formation
What are the different prostate cancer treatments ?
CHECK SLIDE
What gene changes can increase risk of prostate cancer ?
Inherited BRCA1 /BRAC2 gene mutations
Men with lynch syndrome
What are some of the risk factors of prostate cancer ?
SLIDE
What is the PTEN gene ?
P ten is a phosphatase that antagonises the phosphatidylinositol 3 kinase signallig pathway.
PTEN is the only known 3’ phosphatase counteracting the PI3K /AKT pathway
Loss of PTen results in increased growth factor signalling
What is TMPRSS”_ERG fusion
This is a fusion gene which is most frequent in prostate
cause a strong proliferation signal
Outline the androgen receptor signalling (AR)
AR is located in the cytoplasm associated with many chaperone proteins
Testosterone is converted into a more potent agonist as it crosses into the prostate.
DHT binds the AR
testosterone is converted by 5-a -reductase .
DHT then bind s to the AR with higher affinity =dimerisation.
Translocation to the nucleus ,binds DNA in promoter regions
Coactivator recruitment
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