Introduction To Hormone Dependent Cancers: Breast And Prostate Cancer Flashcards
What is a hormone?
A 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 in another part of the body.
Where are the endocrine glands in the body?
Brain - pineal gland, hypothalamus and pituitary glands
Thyroid
Thymus
Pancreas
Adrenal cortex + kidneys
Male (testies) female (ovaries)
What are the 3 main classes of hormones?
Steroids- lipid soluble small molecules (testosterone)
Peptide/proteins (insulin)
Modified amino acids/ amine hormones (adrenaline)
What are steroid hormones synthesised from?
Cholesterol (ingested or synthesised de novo in the body)
Basic four ring steroid backbone structure.
Describe the process of steroid synthesis
Cholesterol > adrenal cortex > gonadal tissues
- main corticosteroids and minerals corticosteroids synthesised in the adrenal cortex
- androgenic and estrogenic precursors released into the bloodstream
- Androgens and oestrogens produced in target tissues
Give some examples of steroid hormone classes?
Androgen (testosterone)
Estrogen (estradiol)
Progestogen (progesterone)
Corticosteroid (cortisol)
Mineral corticosteroids (aldosterone)
What are sex hormones?
Are produced by gonads (ovaries and testies)
Responsible for sexual dimorphism between male and female
Responsible for development of the secondary characteristics (eg. Body hair, growth spurt, breast growth)
What are the. 3 main examples of sex hormones?
Testosterone
Estrogen
Progesterone
What is the effect of oestrogen on females?
Controls the menstrual cycle
Breast tissue development
Fertility
Reproductive organ development
Secondary sexual characteristics
What is the effect of testosterone in males?
Controls reproductive and supportive organs
Development of sexual characteristics in men (deepening of the voice, nobody hair)
How do steroid hormones function?
Systemically - having effects on several tissues at once
What is the role of steroid hormones in cancer?
Steroid hormones can still influence cell growth and function in breast and prostate cancer
Consequently how the disease develops and progresses
The dependence of these tissues on steroids can be exploited when it comes to treatment
What are the 2 most common cancers in the uk?
Breast cancer
Prostate cancer
What are the structural domains of steroid hormones and how do they contribute to they’re function?
Small lipophillic molecule - enter cells by passing through plasma membrane
Bind to nuclear receptors
How are steroid hormones divided into classes?
All steroids bind to a unique nuclear receptor
Describe how steroid hormones work?
- Steroid hormones in the blood enter cells by simple diffusion
- Once inside the cell cytoplasm it binds to a nuclear receptor
- Steroid hormone binding causes a conformational change in the receptor - causing it to become activated
- The steroid hormone complex then translocated into the nucleus
- In the nucleus the steroid receptor binds to DNA at specific binding sites (steroid response elements)
- Steroid response elements are short sequences of DNA found in the promoter region of steroid response genes
- Steroid responsive genes are switched on and unregulated
What is a ligand blinding domain (LBD)?
Binds specific steroid molecules with high affinity
What is a DNA binding domain (DBD)?
Binds specific DNA sequences
What are the key components of nuclear receptor?
Ligand binding domain (LBD)
DNA binding domain (DBD)
Activation function domain (AF1 and AF2)
What is activation function domain (AF1 and AF2)
Recruits gene activation machinery, some receptors have a secondary AF2 domain towards C terminal
What are the key characteristics of nuclear receptors?
Receptors bind steroid hormones they are activated
- they are called ligand-activated receptors
- binding of steroids to the ligand binding domain causes a physical reconstructing of the polypeptide chains in the receptor, activating it
Describe how transcription factors are activated by ligands
- Ligand binding to the ligand binding site causes a shift in a alpha helix, activating the receptor
- Receptor dimerises, moves into the nucleus and binds to specific DNA sequences
- Receptor then recruits DNA modifying enzymes to promoters of hormone responsive genes
What are the 2 zinc fingers domains in the DNA binding domain?
Which are essential for sequence specific DNA binding domains
C1 zinc finger - specific DNA sequence binding
C2 zinc finger - interaction with the DNA phosphate backbone
What do hormones responsive genes include?
Tissue specific genes
Cell cycle
Proliferation genes
Genes involved in tissue development and differentiation
What are hormone response elements?
Are specific DNA sequences found in the promoters of hormone responsive genes
Many are palindromic
Describe the nuclear receptor super family
48 nuclear receptor genes
All share a common domain structure (are thought to arise from a common evolutionary ancestor)
They all share a structure that is actives by ligand binding
What is the female breast?
Apocrine gland that produces milk used to feed an infant
The breast is composed of glands and ducts, which produce the fatty breast milk
What is the female breast comprised of?
Milk producing glands are organised into 15-20 lobes
Within each lobe are lobules where milk is produced?
Milk travels through tiny tubes called ducts
The ducts connect together and become larger ducts and eventually exit the skin via the nipple
What are exocrine glands?
Secrete substances out onto a surface or cavity via ductal structure
What are endocrine glands?
Secrete substances directly into the bloodstream
What are apocrine glands?
Specialised exocrine glands in which a party of cells cytoplasm breaks of releasing contents
What are the 2 components of mammillary epithelium?
Luminal
- form a single layer of polarised epithelium around ductile lumen.
- luminal cells produce milk during lactation
Basal
- comprise of the cells that do not touch the lumen
- basally oriented myoepithelial cells in contact with the basement membrane
- have contractile function during lactation
What are the two major phases of mammillary gland development?
Hormone independent from embryonic development up to puberty
Hormone dependent thereafter during puberty, menstrual cycle and pregnancy
What is the role of Estrogen in normal breasts
Drives the expression og genes involved in cellular proliferation and differentiation
During puberty- ductal elongation and triggers side branching
Adult Oestrogen - allows for the maintenance for mammary gland tissue + primes tissue for effects of progesterone during pregnancy for milk production
What is breast cancer?
Tumour forms in the breast
Breast cancer starts most commonly in the cells that line the milk ducts
1/8 women may develop it in they’re lifestyle
Main risks are age, lifestyle, and genetic familial factors
Describe the aetiology of breast cancer
Age - risk factor for breast cancer increases with age (most after 50)
Genetic mutations - people with genes BRAC1 and BRAC2 are at higher risk of developing breast and ovarian cancer
Reproductive history - early onset of menstrual cycle before 12 years + starting menopause at 55yrs + pregnancy after 30 years + never having full term pregnancy
Previous treatment using radiotherapy to the chest or breasts before age 30 have higher risk of getting breast cancer late in life
Not being physically active
Overweight or obese
Taking hormones
Drinking alcohol
What is ductal breast carcinoma in situ (DCIS)?
Cancer cells develop within the ducts of the breast but remain within the ducts
Cancer cells have not developed the ability to spread outside these ducts into the teh surrounding breast tissue
What is lobular breast carcinoma in situ (LCIS)?
A uncommon condition in which abnormal cells form in the milk glands (lobules) in the breast
Isn’t cancer but being diagnosed could increase ur risk of developing breast cancer
Where do the majority of breast cancers arise?
From luminal cells (epithelial cells of the lumen)
Express the oestrogen receptor (ER)
What is the difference between ER positive and ER negative breast cancers?
Majority are ER positive and have a good prognosis
ER negative have a relatively poor prognosis and cannot be treated hormonally so patients are given more conventional therapies
What is the role of progesterone in breast cancer?
Progesterone receptor is a indicator of Estrogen activity
Progesterone is becoming more of a target for cancer therapy as in some subtypes it may reduce cell growth
What does the role of ER have in breast cancer?
The ER signalling pathway is subverted and becomes uncontrolled
ER ability to bind to DNA and open chromatin is used to transcribe many genes and mRNAs
ER then governs cancer cell proliferation and controls many genes involved in metastasis, invasion and adhesion.
How can ER be targeted in breast cancer treatment?
Breast cancer cells are Estrogen sensitive and dependent meaning Estrogen are essential for driving the growth of breast cancer cells.
Inhibiting Estrogen signalling inhibits cancer growth
How is ER signalling inhibited in breast cancer patients?
Biopsy samples are analysed for ER expression to determine weather it’s positive or negative
Specific treatments are given to block ER activity
How does the Estrogen signalling pathway work?
- Bind to receptor
- AF1 and AF2 activated - recruited proteins for gene activation
- Full gene transcription - breast cancer growth
How does fulvestrant (Faslodex) inhibit the ER pathway?
It’s a analogue of estradiol
Has a greater binding affinity
Acts as a competitive inhibitor for the binding of estradiol to ER - impairs receptor dimerisation and translocation
The ER implement that enters the nucleus is transcriptionally inactive because both AF1 and AF2 are disabled
The complex is unstable, resulting in accelerated degradation of the ER protein
How does Tamoxifen inhibit the ER pathway?
Binds the ER at the ligand binding site
Tamoxifen is a partial agonist but does not cause the full activation of ER - activates ER in liver and uterus but acts as a ANTAGONIST in breast tissue
Tamoxifen is a selective Estrogen receptor modulator (SERM)
Tamoxifen bound ER does not fold and AF2 domain doesn’t function
What is the process by which Tamoxifen Bound ER inhibits the ER signalling pathway?
Normally, estradiol binds deep within a pocket in the receptor and is covered by a loop of protein chain which activates cell growth
When tamoxifen binds to ER ligand binding site - partially active
the extra tail of tamoxifen is too bulky and the receptor loop is unable to adopt its active conformation.
Receptor undergoes a conformational change only activating the AF1 domain.
Partially activating transcription
What is a alternative source of Oestrogens during menopause?
Conversion of androgens by aromatase enzyme
Aromatase is present in many organs (brain, skin, bone)
What is the type 1 aromatase inhibitor mechanism?
Androgen analogues
Bind irreversibly to aromatase - “suicide inhibitors”
Duration of inhibitory effect is primarily dependent on the rate of de novo synthesis of aromatase
What is the type 2 aromatase inhibitor mechanism?
Contains a functional group within the ring structure that binds the heme iron of the cytochrome P450 (of aromatase)
Interferes with the hydroxylation reactions
What is the function of the prostate?
Produce prostatic fluid that creates semen when mixed with the sperm produced by testes
Luminal epithelial cells surrounding duct lumens
Basal epithelial cells
What are the phases of normal prostate development?
- Hormone independent from embryonic until puberty
- Enlargement during puberty
- Hormone-dependent maintenance thereafter in adulthood
- Reactivation of prostate growth in old age - prostate cancer
What are the symptoms of prostate cancer?
- frequent trips to urinate
- poor urinary stream
- urgent need to urinate
- hesitancy whilst urinating
- lower back pain
- blood in the urine
Where does prostate cancer start?
Originate in luminal epithelial cells - hyper proliferation
What are the three ways to detect prostate cancer?
1) digital rectal examination (DRE)
2) PSA test
3) ultrasound
What are stages of prostate cancer?
T1 - small, localised tumour
T2 - palpable tumour
T3 - escape from prostate gland
T4 - local spread to pelvic region
What does the N number represent in lymph node tumours?
N0 - no cancer cells found in any lymph nodes
N1 - 1 positive lymph node < 2 cm across
N2 - >1 positive lymph node one between 2-5cm
N3 - any positive lymph node > 5 cm across
What does the M number represent in metastasis ?
M1a - Non-regional lymph nodes
M1b - bone
M1c - other sites
What does prostate gland look like under a microscope?
Loss of glandular structure / irregular structure
Describe how the Gleason grading system used to asses prostate cancer
Prostate biopsy samples are examined by a clinical histologist
Cancer staging predicts prognosis
Cancers with higher Gleason score are more aggressive and have a worse prognosis
What are the four treatments for prostate cancer?
“Watchful waiting” - low grade tumour, older patients
Radical prostate - stage T1 or T2
Radical radiotherapy - external up to T3 or internal implants for T1/2
Hormone therapy - +/- prosectomy or radial radiotherapy, metastasis prostate
What are the risk factors for prostate cancer?
Age - rare in men younger than 40
Race/Ethnicity - develops more often in African-American men and in Caribbean men
Geography - most common in North America, north-western Europe, Australia, and on Caribbean islands
Family history - mostly occur in men without a family history of it but can run in some families
Gene changes/ inherited - inherited BRAC1 and BRAC2 gene mutations or lynch syndrome
Diet - a lot of dairy products may play a role
Obesity
What genetic changes are involved in prostate cancer?
Somatic copy number alterations - gain or loss of genetic material
Structural rearrangements - improper repair of DNA breaks leads to chromosome rearrangements
Point mutations - changes in specific nucleotides - ulterior gene products
Single nucleotide polymorphisms (SNPs) - variations in a single nucleotide between individual’s or chromosomes
miRNA - small, non-coding RNA molecules
What is PTEN?
A phosphatase that antagonises the 3-kinase signalling pathway
PTEN is the Only Known 3 phosphatase counteracting the PI3K/AKT pathway
Loss of PTEN results in increased growth factor signalling
Where are testosterone receptors located in the prostate gland?
Brown staining for androgen receptor expression in the luminal epithelial cells
In cytoplasm
Associated with chaperone proteins
Describe the androgen receptor AR signalling pathway
- Testosterone is converted to a more potent agonist as it enters prostate cells
- Dihydrotestosterone (DHT) then binds to AR
- Dimerisation occurs
- DNA binding
- COACTIVATOR RECRUITMENT
How can AR be a target for prostate cancer treatment?
Prostate gland is androgen sensitive and dependent tissue
Switching of AR signalling, switches off cancer growth
Describe the inhibition of testosterone synthesis for prostate cancer
adrenal androgen production can be inhibited
depriving the testes of testosterone
Eg.
Abiraterone acetate - prevents cholesterol being converted to adrenal androgens
Goserelin - super agonist
Abarelix - antagonist
Describe the inhibition of testosterone conversion to DHT
5 alpha reductase
Inhibit the conversion of testosterone to DHT
Used for begnin hyperplasia
Describe the inhibition of androgen binding to the receptor
Competitive inhibition of androgen binding to the receptor
Helix 12 cannot fold over
Creating inactive transcription factor
Eg. Flutamide, Nilutamide
How effective are hormone therapies for cancer?
Normally hormone therapies work well BUT over time these therapies begin to fail and patients relapse with hormone refractory cancers
How can hormone overproduction occur?
Some breast and prostate tumour start to synthesis their own steroid hormones
How do ligand binding site mutations allow other hormones to bind?
Ligand binding site mutations make the receptor promiscuous
Describe the process of receptor amplification
- Signal amplification and increased sensitivity to low hormone levels
- Receptor phosphorylation / activation in the absence of ligand
- Androgen receptor transcription variants - activation in absence of ligand
- Receptor bypass - unknown mechanisms
- Receptor cofactor amplification - signal from steroid receptors in response to a low level of steroid hormone
- Antagonist become agonist via LBD mutations - can become potent activators of a mutant androgen receptor
